Irak inhibitors and uses thereof

ABSTRACT

The present invention provides arylo-fused thienopyrimidine compounds, compositions thereof, and methods of using the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. provisional patentapplication Ser. No. 61/670,372, filed Jul. 11, 2012, and U.S.provisional patent application Ser. No. 61/682,627, filed Aug. 13, 2012,the entirety of each of which is incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds and methods useful forinhibiting one or more interleukin-1 receptor-associated kinases(“IRAK”). The invention also provides pharmaceutically acceptablecompositions comprising compounds of the present invention and methodsof using said compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recentyears by a better understanding of the structure of enzymes and otherbiomolecules associated with diseases. One important class of enzymesthat has been the subject of extensive study is the protein kinasefamily.

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a variety of signaltransduction processes within the cell. Protein kinases are thought tohave evolved from a common ancestral gene due to the conservation oftheir structure and catalytic function. Almost all kinases contain asimilar 250-300 amino acid catalytic domain. The kinases may becategorized into families by the substrates they phosphorylate (e.g.,protein-tyrosine, protein-serine/threonine, lipids, etc.).

In general, protein kinases mediate intracellular signaling by effectinga phosphoryl transfer from a nucleoside triphosphate to a proteinacceptor that is involved in a signaling pathway. These phosphorylationevents act as molecular on/off switches that can modulate or regulatethe target protein biological function. These phosphorylation events areultimately triggered in response to a variety of extracellular and otherstimuli. Examples of such stimuli include environmental and chemicalstress signals (e.g., osmotic shock, heat shock, ultraviolet radiation,bacterial endotoxin, and H₂O₂), cytokines (e.g., interleukin-1 (IL-1),interleukin-8 (IL-8) and tumor necrosis factor α (TNF-α)), and growthfactors (e.g., granulocyte macrophage-colony-stimulating factor(GM-CSF), and fibroblast growth factor (FGF)). An extracellular stimulusmay affect one or more cellular responses related to cell growth,migration, differentiation, secretion of hormones, activation oftranscription factors, muscle contraction, glucose metabolism, controlof protein synthesis, and regulation of the cell cycle.

Many diseases are associated with abnormal cellular responses triggeredby kinase-mediated events. These diseases include, but are not limitedto, autoimmune diseases, inflammatory diseases, bone diseases, metabolicdiseases, neurological and neurodegenerative diseases, cancer,cardiovascular diseases, allergies and asthma, Alzheimer's disease, andhormone-related diseases. Accordingly, there remains a need to findprotein kinase inhibitors useful as therapeutic agents.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCertain Embodiments of the Invention

Compounds of the present invention, and compositions thereof, are usefulas inhibitors of one or more IRAK protein kinases. In some embodiments,a provided compound inhibits IRAK-1 and IRAK-4.

The binding pocket of IRAK-4 contains a plurality of hydration sites,each of which is occupied by a single molecule of water. Each of thesewater molecules has a stability rating associated with it. As usedherein, the term “stability rating” refers to a numerical calculationwhich incorporates the enthalpy, entropy, and free energy valuesassociated with each water molecule. This stability rating allows for ameasurable determination of the relative stability of water moleculesthat occupy hydration sites in the binding pocket of IRAK-4.

Water molecules occupying hydration sites in the binding pocket ofIRAK-4 having a stability rating of >2.5 kcal/mol are referred to as“unstable waters.”

Without wishing to be bound by any particular theory, it is believedthat displacement or disruption of an unstable water molecule (i.e., awater molecule having a stability rating of >2.5 kcal/mol), orreplacement of a stable water (i.e., a water molecule having a stabilityrating of <1 kcal/mol), by an inhibitor results in tighter binding ofthat inhibitor. Accordingly, inhibitors designed to displace one or moreunstable water molecules (i.e., those unstable water molecules notdisplaced by any known inhibitor) will be a tighter binder and,therefore, more potent inhibitor as compared to an inhibitor that doesnot displace unstable water molecules.

It was surprisingly found that provided compounds displace or disruptone or more unstable water molecules. In some embodiments, a providedcompound displaces or disrupts at least two unstable water molecules.

In certain embodiments, the present invention provides a compound offormula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   Ring A is a 3-7 membered saturated or partially unsaturated    carbocyclic ring or a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-3 heteroatoms independently    selected from nitrogen, oxygen, and sulfur;-   n is 0-4;-   each R¹ is independently —R, halogen, —CN, —NO₂, —OR, —CH₂OR, —SR,    —N(R)₂, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)₂,    —C(O)N(R)—OR, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)₂, Cy, or    —N(R)S(O)₂R; or R¹ is selected from one of the following formulas:

-    or    -   two R¹ groups are taken together with their intervening atoms to        form an optionally substituted 4-7 membered fused, spiro-fused,        or bridged bicyclic ring having 0-2 heteroatoms independently        selected from nitrogen, oxygen, and sulfur;-   each Cy is an optionally substituted ring selected from a 3-7    membered saturated or partially unsaturated carbocyclic ring or a    4-7 membered saturated or partially unsaturated heterocyclic ring    having 1-3 heteroatoms independently selected from nitrogen, oxygen,    and sulfur;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, or 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   Ring B is selected from a benzo fused ring and a 5-6 membered    heteroaromatic fused ring having 1-3 heteroatoms independently    selected from nitrogen, oxygen, and sulfur; wherein said Ring B may    be optionally substituted by one or more oxo, thiono, or imino    groups;-   m is 0-4;-   p is 0-2;-   W is N or —C(R³)—;-   R^(z) is R, CN, NO₂, halogen, —C(O)N(R)₂, —C(O)OR, —C(O)R, —N(R)₂,    —N(R)C(O)OR, —N(R)C(O)N(R)₂, —OR, or —S(O)₂N(R)₂;-   R³ is hydrogen, halogen, —CN, C₁₋₄ aliphatic, C₁₋₄ haloaliphatic,    —OR, —C(O)R, or —C(O)N(R)₂;-   L¹ is a covalent bond or a C₁₋₆ bivalent hydrocarbon chain wherein    one or two methylene units of the chain are optionally and    independently replaced by —N(R)—, —N(R)C(O)—, —C(O)N(R)—,    —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)—    or —S(O)₂—;-   each L² is independently a covalent bond or a C₁₋₆ bivalent    hydrocarbon chain wherein one or two methylene units of the chain    are optionally and independently replaced by —N(R)—, —N(R)C(O)—,    —C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—,    —S—, —S(O)— or —S(O)₂—;-   each R⁴ is independently halogen, —CN, —NO₂, —OR, —SR, —N(R)₂,    —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)₂,    —N(R)C(O)R, —N(R)C(O)N(R)₂, —C(O)N(R)OR, —N(R)C(O)OR,    —N(R)S(O)₂N(R)₂, —N(R)S(O)₂R, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, or 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two -L²(R⁴)_(p)—R⁴ groups are taken together with their        intervening atoms to form an optionally substituted 4-7 membered        fused, or bridged bicyclic ring having 0-2 heteroatoms        independently selected from nitrogen, oxygen, and sulfur.

2. Compounds and Definitions

Compounds of the present invention include those described generallyherein, and are further illustrated by the classes, subclasses, andspecies disclosed herein. As used herein, the following definitionsshall apply unless otherwise indicated. For purposes of this invention,the chemical elements are identified in accordance with the PeriodicTable of the Elements, CAS version, Handbook of Chemistry and Physics,75^(th) Ed. Additionally, general principles of organic chemistry aredescribed in “Organic Chemistry”, Thomas Sorrell, University ScienceBooks, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th)Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001,the entire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Suitable aliphatic groups include, but are not limited to, linear orbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

As used herein, the term “bridged bicyclic” refers to any bicyclic ringsystem, i.e. carbocyclic or heterocyclic, saturated or partiallyunsaturated, having at least one bridge. As defined by IUPAC, a “bridge”is an unbranched chain of atoms or an atom or a valence bond connectingtwo bridgeheads, where a “bridgehead” is any skeletal atom of the ringsystem which is bonded to three or more skeletal atoms (excludinghydrogen). In some embodiments, a bridged bicyclic group has 7-12 ringmembers and 0-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur. Such bridged bicyclic groups are well known in theart and include those groups set forth below where each group isattached to the rest of the molecule at any substitutable carbon ornitrogen atom. Unless otherwise specified, a bridged bicyclic group isoptionally substituted with one or more substituents as set forth foraliphatic groups. Additionally or alternatively, any substitutablenitrogen of a bridged bicyclic group is optionally substituted.Exemplary bridged bicyclics include:

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

As used herein, the term “cyclopropylenyl” refers to a bivalentcyclopropyl group of the following structure:

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic orbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains 3 to 7 ring members. The term “aryl” may beused interchangeably with the term “aryl ring.” In certain embodimentsof the present invention, “aryl” refers to an aromatic ring system whichincludes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl andthe like, which may bear one or more substituents. Also included withinthe scope of the term “aryl,” as it is used herein, is a group in whichan aromatic ring is fused to one or more non-aromatic rings, such asindanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono- or bicyclic. The term “heteroaryl” may beused interchangeably with the terms “heteroaryl ring,” “heteroarylgroup,” or “heteroaromatic,” any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms independently selected from oxygen, sulfur ornitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (asin pyrrolidinyl), or ⁺NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. Theterm “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(◯); —(CH₂)₀₋₄OR^(◯); —O(CH₂)₀₋₄R^(◯), —O—(CH₂)₀₋₄C(O)OR^(◯);—(CH₂)₀₋₄CH(OR^(◯))₂; —(CH₂)₀₋₄SR^(◯); —(CH₂)₀₋₄Ph, which may besubstituted with R^(◯); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(◯); —CH═CHPh, which may be substituted with R^(◯);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(◯); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(◯))₂; —(CH₂)₀₋₄N(R^(◯))C(O)R^(◯);—N(R^(◯))C(S)R^(◯); —(CH₂)₀₋₄N(R^(◯))C(O)NR^(◯) ₂; —N(R^(◯))C(S)NR^(◯)₂; —(CH₂)₀₋₄N(R^(◯))C(O)OR^(◯); —N(R^(◯))N(R^(◯))C(O)R^(◯);—N(R^(◯))N(R^(◯))C(O)NR^(◯) ₂; —N(R^(◯))N(R^(◯))C(O)OR^(◯);—(CH₂)₀₋₄C(O)R^(◯); —C(S)R^(◯); —(CH₂)₀₋₄C(O)OR^(◯);—(CH₂)₀₋₄C(O)SR^(◯); —(CH₂)₀₋₄C(O)OSiR^(◯) ₃; —(CH₂)₀₋₄OC(O)R^(◯);—OC(O)(CH₂)₀₋₄SR—, SC(S)SR^(◯); —(CH₂)₀₋₄SC(O)R^(◯); —(CH₂)₀₋₄C(O)NR^(◯)₂; —C(S)NR^(◯) ₂; —C(S)SR^(◯); —SC(S)SR^(◯), —(CH₂)₀₋₄OC(O)NR^(◯) ₂;—C(O)N(OR^(◯))R^(◯); —C(O)C(O)R^(◯); —C(O)CH₂C(O)R^(◯);—C(NOR^(◯))R^(◯); —(CH₂)₀₋₄SSR^(◯); —(CH₂)₀₋₄S(O)₂R^(◯);—(CH₂)₀₋₄S(O)₂OR^(◯); —(CH₂)₀₋₄OS(O)₂R^(◯); —S(O)₂NR^(◯) ₂;—(CH₂)₀₋₄S(O)R^(◯); —N(R^(◯))S(O)₂NR^(◯) ₂; —N(R^(◯))S(O)₂R^(◯);—N(OR^(◯))R^(◯); —C(NH)NR^(◯) ₂; —P(O)₂R^(◯); —P(O)R^(◯) ₂; —OP(O)R^(◯)₂; —OP(O)(OR^(◯))₂; SiR^(◯) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(◯))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(◯))₂, wherein each R^(◯) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(◯), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(◯) (or the ring formed by takingtwo independent occurrences of R^(◯) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(), —(haloR^()),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(), —(CH₂)₀₋₂CH(OR^())₂; —O(haloR^()), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(),—(CH₂)₀₋₂SR^(), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(),—(CH₂)₀₋₂NR^() ₂, —NO₂, —SiR^() ₃, OSiR^() ₃, —C(O)SR^(), —(C₁₋₄straight or branched alkylene)C(O)OR^(), or —SSR^() wherein each R^()is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur. Suitable divalent substituents on asaturated carbon atom of R^(◯) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(), -(haloR^()), —OH, —OR^(), —O(haloR^()), —CN, —C(O)OH,—C(O)OR^(), —NH₂, —NHR^(), —NR^() ₂, or —NO₂, wherein each R^() isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(), -(haloR^()), —OH, —OR^(), —O(haloR^()), —CN,—C(O)OH, —C(O)OR^(), —NH₂, —NHR^(), —NR^() ₂, or —NO₂, wherein eachR^() is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention. In certainembodiments, a warhead moiety, R¹, of a provided compound comprises oneor more deuterium atoms. In certain embodiments, Ring B of a providedcompound may be substituted with one or more deuterium atoms.

As used herein, the term “inhibitor” is defined as a compound that bindsto and/or inhibits IRAK-4 with measurable affinity. In certainembodiments, an inhibitor has an IC₅₀ and/or binding constant of lessthan about 50 μM, less than about 1 μM, less than about 500 nM, lessthan about 100 nM, less than about 10 nM, or less than about 1 nM.

A compound of the present invention may be tethered to a detectablemoiety. It will be appreciated that such compounds are useful as imagingagents. One of ordinary skill in the art will recognize that adetectable moiety may be attached to a provided compound via a suitablesubstituent. As used herein, the term “suitable substituent” refers to amoiety that is capable of covalent attachment to a detectable moiety.Such moieties are well known to one of ordinary skill in the art andinclude groups containing, e.g., a carboxylate moiety, an amino moiety,a thiol moiety, or a hydroxyl moiety, to name but a few. It will beappreciated that such moieties may be directly attached to a providedcompound or via a tethering group, such as a bivalent saturated orunsaturated hydrocarbon chain. In some embodiments, such moieties may beattached via click chemistry. In some embodiments, such moieties may beattached via a 1,3-cycloaddition of an azide with an alkyne, optionallyin the presence of a copper catalyst. Methods of using click chemistryare known in the art and include those described by Rostovtsev et al.,Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., BioconjugateChem., 2006, 17, 52-57.

As used herein, the term “detectable moiety” is used interchangeablywith the term “label” and relates to any moiety capable of beingdetected, e.g., primary labels and secondary labels. Primary labels,such as radioisotopes (e.g., tritium, ³²P, ³³P, ³⁵S, or ¹⁴C), mass-tags,and fluorescent labels are signal generating reporter groups which canbe detected without further modifications. Detectable moieties alsoinclude luminescent and phosphorescent groups.

The term “secondary label” as used herein refers to moieties such asbiotin and various protein antigens that require the presence of asecond intermediate for production of a detectable signal. For biotin,the secondary intermediate may include streptavidin-enzyme conjugates.For antigen labels, secondary intermediates may include antibody-enzymeconjugates. Some fluorescent groups act as secondary labels because theytransfer energy to another group in the process of nonradiativefluorescent resonance energy transfer (FRET), and the second groupproduces the detected signal.

The terms “fluorescent label”, “fluorescent dye”, and “fluorophore” asused herein refer to moieties that absorb light energy at a definedexcitation wavelength and emit light energy at a different wavelength.Examples of fluorescent labels include, but are not limited to: AlexaFluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, AlexaFluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, AlexaFluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL,BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568,BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY650/665), Carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue,Cascade Yellow, Coumarin 343, Cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5),Dansyl, Dapoxyl, Dialkylaminocoumarin,4′,5′-Dichloro-2′,7′-dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosin,Fluorescein, FAM, Hydroxycoumarin, IRDyes (IRD40, IRD 700, IRD 800),JOE, Lissamine rhodamine B, Marina Blue, Methoxycoumarin,Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, RhodamineGreen, Rhodamine Red, Rhodol Green,2′,4′,5′,7′-Tetra-bromosulfone-fluorescein, Tetramethyl-rhodamine (TMR),Carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

The term “mass-tag” as used herein refers to any moiety that is capableof being uniquely detected by virtue of its mass using mass spectrometry(MS) detection techniques. Examples of mass-tags include electrophorerelease tags such asN-[3-[4′-[(p-Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecoticAcid, 4′-[2,3,5,6-Tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone, and their derivatives. The synthesis and utility of thesemass-tags is described in U.S. Pat. Nos. 4,650,750, 4,709,016,5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270.Other examples of mass-tags include, but are not limited to,nucleotides, dideoxynucleotides, oligonucleotides of varying length andbase composition, oligopeptides, oligosaccharides, and other syntheticpolymers of varying length and monomer composition. A large variety oforganic molecules, both neutral and charged (biomolecules or syntheticcompounds) of an appropriate mass range (100-2000 Daltons) may also beused as mass-tags.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, means a measurable change in an IRAK protein kinase activitybetween a sample comprising a compound of the present invention, orcomposition thereof, and an IRAK protein kinase, and an equivalentsample comprising an IRAK protein kinase, in the absence of saidcompound, or composition thereof

3. Description of Exemplary Embodiments

As described above, in certain embodiments, the present inventionprovides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   Ring A is a 3-7 membered saturated or partially unsaturated    carbocyclic ring or a 4-7 membered saturated or partially    unsaturated heterocyclic ring having 1-3 heteroatoms independently    selected from nitrogen, oxygen, and sulfur;-   n is 0-4;-   each R¹ is independently —R, halogen, —CN, —NO₂, —OR, —CH₂OR, —SR,    —N(R)₂, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)₂,    —C(O)N(R)—OR, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)₂, Cy, or    —N(R)S(O)₂R, or R¹ is selected from one of the following formulas:

-    or    -   two R¹ groups are taken together with their intervening atoms to        form an optionally substituted 4-7 membered fused, spiro-fused,        or bridged bicyclic ring having 0-2 heteroatoms independently        selected from nitrogen, oxygen, and sulfur;-   each Cy is an optionally substituted ring selected from a 3-7    membered saturated or partially unsaturated carbocyclic ring or a    4-7 membered saturated or partially unsaturated heterocyclic ring    having 1-3 heteroatoms independently selected from nitrogen, oxygen,    and sulfur;-   each R is independently hydrogen, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, or 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;-   Ring B is selected from a benzo fused ring and a 5-6 membered    heteroaromatic fused ring having 1-3 heteroatoms independently    selected from nitrogen, oxygen, and sulfur; wherein said Ring B may    be optionally substituted by one or more oxo, thiono, or imino    groups;-   m is 0-4;-   p is 0-2;-   W is N or —C(R³)—;-   R^(z) is R, CN, NO₂, halogen, —C(O)N(R)₂, —C(O)OR, —C(O)R, —N(R)₂,    —N(R)C(O)OR, —N(R)C(O)N(R)₂, —OR, or —S(O)₂N(R)₂;-   R³ is hydrogen, halogen, —CN, C₁₋₄ aliphatic, C₁₋₄ haloaliphatic,    —OR, —C(O)R, or —C(O)N(R)₂;-   L¹ is a covalent bond or a C₁₋₆ bivalent hydrocarbon chain wherein    one or two methylene units of the chain are optionally and    independently replaced by —N(R)—, —N(R)C(O)—, —C(O)N(R)—,    —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)—    or —S(O)₂—;-   each L² is independently a covalent bond or a C₁₋₆ bivalent    hydrocarbon chain wherein one or two methylene units of the chain    are optionally and independently replaced by —N(R)—, —N(R)C(O)—,    —C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—,    —S—, —S(O)— or —S(O)₂—;-   each R⁴ is independently halogen, —CN, —NO₂, —OR, —SR, —N(R)₂,    —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)₂,    —N(R)C(O)R, —N(R)C(O)N(R)₂, —C(O)N(R)OR, —N(R)C(O)OR,    —N(R)S(O)₂N(R)₂, —N(R)S(O)₂R, or an optionally substituted group    selected from C₁₋₆ aliphatic, phenyl, 4-7 membered saturated or    partially unsaturated heterocyclic having 1-2 heteroatoms    independently selected from nitrogen, oxygen, and sulfur, or 5-6    membered heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, and sulfur, or:    -   two -L²(R⁴)_(p)—R⁴ groups are taken together with their        intervening atoms to form an optionally substituted 4-7 membered        fused, or bridged bicyclic ring having 0-2 heteroatoms        independently selected from nitrogen, oxygen, and sulfur;

As defined generally above, the Ring A group of formula I is a 3-7membered saturated or partially unsaturated carbocyclic ring or a 4-7membered saturated or partially unsaturated heterocyclic ring having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, Ring A is a 3-7 membered saturated or partiallyunsaturated carbocyclic ring. In certain embodiments, Ring A is a 4-7membered saturated or partially unsaturated heterocyclic ring having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, Ring A is a 3-7 membered saturated carbocyclicring. In certain embodiments, Ring A is cyclopentyl or cyclohexyl.

In certain embodiments, Ring A is a 4-7 membered saturated heterocyclicring having 1-3 heteroatoms independently selected from nitrogen,oxygen, and sulfur. In certain embodiments, Ring A is a 5-6 memberedsaturated heterocyclic ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. In certain embodiments, RingA is piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,tetrahydropyranyl, or tetrahydrofuranyl.

As defined generally above, the n group of formula I is 0-4. In someembodiments, n is 0. In other embodiments, n is 1-4. In certainembodiments, n is 1 or 2.

As defined generally above, each R¹ group of formula I is independently—R, halogen, —CN, —NO₂, —OR, —CH₂OR, —SR, —N(R)₂, —S(O)₂R, —S(O)₂N(R)₂,—S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)—OR, —N(R)C(O)R,—N(R)C(O)R, —N(R)C(O)N(R)₂, Cy, or —N(R)S(O)₂R; or R¹ is selected fromone of the following formulas:

ortwo R¹ groups are taken together with their intervening atoms to form anoptionally substituted 4-7 membered fused, spiro-fused, or bridgedbicyclic ring having 0-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur.

In certain embodiments, R¹ is R, —OR, —N(R)₂, —C(O)OR, —C(O)N(R)₂,—C(O)N(R)—OR, —N(R)C(O)R, —S(O)₂N(R)₂, Cy, or —N(R)C(O)OR. In someembodiments, R¹ is —C(O)NH₂, —C(O)NHCH₃, —C(O)NH—OH, —CH₃, —CH₂CH₃,—S(O)₂t-butyl, —OH, —C(O)OH, —NH₂, —NHCH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—NHC(O)CH₃, or —CH₂phenyl. In certain embodiments, R¹ is selected fromone of the following formulas:

In certain embodiments, R¹ is Cy. In certain embodiments, R¹ is —N(R)₂.Exemplary R¹ groups include those depicted in Table 1.

In some embodiments, the present invention provides a compound offormula I wherein two R¹ groups are taken together with theirintervening atoms to form an optionally substituted 4-7 membered fused,spiro-fused, or bridged bicyclic ring having 0-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In certainembodiments, two R¹ groups on adjacent carbon atoms are taken togetherto form an optionally substituted 4-7 membered ring fused to Ring A. Inother embodiments, two R¹ groups on the same carbon atom are takentogether to form an optionally substituted 4-7 membered spiro-fusedring. In other embodiments, two R¹ groups on non-adjacent carbon atomsare taken together to form an optionally substituted bridged bicyclicring with Ring A.

As defined generally above, Cy is an optionally substituted ringselected from a 3-7 membered saturated or partially unsaturatedcarbocyclic ring or a 4-7 membered saturated or partially unsaturatedheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur.

In some embodiments, Cy is a 3-7 membered saturated carbocyclic ring. Incertain embodiments, Cy is a 4-7 membered saturated heterocyclic ringcontaining 1-2 heteroatoms independently selected from nitrogen, oxygenand sulfur. In certain embodiments Cy is a spirobicyclic 7-memberedring. In certain embodiments, Cy is morpholinyl, pyrrolidinyl,azetidinyl, piperidinyl or piperazinyl.

One of ordinary skill in the art will appreciate that an R¹ substituenton a saturated carbon of Ring A forms a chiral center. In someembodiments, that chiral center is in the (R) configuration. In otherembodiments, that chiral center is in the (S) configuration.

As defined generally above, the L¹ group of formula I is a covalent bondor a C₁₋₆ bivalent hydrocarbon chain wherein one or two methylene unitsof the chain are optionally and independently replaced by —N(R)—,—N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—,—C(O)O—, —S—, —S(O)— or —S(O)₂—. In some embodiments, L¹ is a covalentbond. In other embodiments, L¹ is a C₁₋₆ bivalent hydrocarbon chainwherein one or two methylene units of the chain are optionally andindependently replaced by —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—,—S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)₂—.

In some embodiments, L¹ is —NH— (i.e., a C₁ bivalent hydrocarbon chainwherein the methylene unit is replaced by —NH—), —O—, —CH₂O—, —OCH₂—,—NHC(O)—, —CH₂NH—, or —NHCH₂—. In some embodiments, L¹ is —O—. In someembodiments, L¹ is —N(R)—. In some embodiments, L¹ is —N(R)CH₂—. In someembodiments L¹ is —OCH₂—. Exemplary L¹ groups include those depicted inTable 1.

As defined generally above, the Ring B group of formula I is a benzofused ring; or a 5-6 membered heteroaromatic fused ring having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, Ring B is a benzo fused ring. In certain embodiments,Ring B is a 5-6 membered heteroaromatic fused ring having 1-3heteroatoms independently selected from nitrogen, oxygen and sulfur. Incertain embodiments, Ring B is a 6 membered heteroaromatic fused ringhaving 1-2 nitrogens. In certain embodiments, Ring B is a pyrido fusedring, a pyrimidino fused ring, pyridazino or pyrazino fused ring. Incertain embodiments, Ring B is a triazino fused ring. In certainembodiments, Ring B is a 5 membered heteroaromatic fused ring containing1-2 heteroatoms independently selected from oxygen, nitrogen and sulfur.In some embodiments, Ring B is a pyrrolo fused ring, a thiopheno fusedring, a furano fused ring, a thiazolofused ring, an isothiazolo fusedring, an imidazolo fused ring, a pyrazolo fused ring, an oxazolo fusedring, an isoxazolo fused ring. In certain embodiments Ring B is a 5-6membered heteroaromatic ring substituted with one or more oxo, thiono orimino groups.

As defined generally above, the m group of formula I is 0-4. In otherembodiments, m is 1-4. In certain embodiments, m is 0. In certainembodiments, m is 1. In certain embodiments, m is 2.

As defined generally above W is N or is N or —C(R³)—. In someembodiments W is N. In some embodiments, W is —C(R³)—.

As defined generally above R³ is hydrogen, halogen, —CN, C₁₋₄ aliphatic,C₁₋₄ haloaliphatic, —OR, —C(O)R, or —C(O)N(R)₂. In some embodiments, R3is hydrogen.

As defined generally above, each L² is independently a covalent bond ora C₁₋₆ bivalent hydrocarbon chain wherein one or two methylene units ofthe chain are optionally and independently replaced by —N(R)—,—N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—,—C(O)O—, —S—, —S(O)— or —S(O)₂—.

In certain embodiments each L² is independently a covalent bond. In someembodiments each L² is a C₁₋₃ bivalent hydrocarbon chain wherein one ortwo methylene units of the chain are optionally and independentlyreplaced by —C(O)N(R)—, —O—, —C(O)—, —S—, —S(O)— or —S(O)₂—. In certainembodiments, L² is methylene. In certain embodiments, L² is —CH₂—C(O)—.In certain embodiments, L² is a C₂ hydrocarbon chain substituted with ahydroxyl group (—CH₂CH(OH)—).

As defined generally above, each R⁴ is independently halogen, —CN, —NO₂,—OR, —SR, —N(R)₂, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR,—C(O)N(R)₂, —N(R)C(O)R, —N(R)C(O)N(R)₂, —C(O)N(R)OR, —N(R)C(O)OR,—N(R)S(O)₂N(R)₂, —N(R)S(O)₂R, or an optionally substituted groupselected from C₁₋₆ aliphatic, phenyl, 4-7 membered saturated orpartially unsaturated heterocyclic having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, or 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur, and: two -L²(R⁴)_(p)—R⁴ groups are taken togetherwith their intervening atoms to form an optionally substituted 4-7membered fused, spiro-fused, or bridged bicyclic ring having 0-2heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, each R⁴ is independently —CN, —OR, —SR, —S(O)R,—S(O)₂R, —C(O)N(R)₂, —N(R)C(O)R, or an optionally substituted groupselected from C₁₋₆ aliphatic, phenyl, 4-7 membered saturated orpartially unsaturated heterocyclic having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, or 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur. In certain embodiments, each R⁴ is independently—CN, —OR, —SR, —S(O)R, —S(O)₂R, —C(O)N(R)₂, or —N(R)C(O)R. In certainembodiments R⁴ is an optionally substituted group selected from C₁₋₆aliphatic, 4-7 membered saturated or partially unsaturated heterocyclichaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In certainembodiments R⁴ is hydroxyl. In certain embodiments R⁴ is —C(O)N(R)₂.

In some embodiments, the present invention provides a compound offormula I wherein two -L²(R⁴)_(p)—R⁴ groups are taken together withtheir intervening atoms to form an optionally substituted 4-7 memberedfused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In certainembodiments, two -L²-R⁴ groups on adjacent carbon atoms are takentogether to form an optionally substituted 4-7 membered ring fused toRing B. In other embodiments, two -L²(R⁴)_(p)—R⁴ groups on non-adjacentcarbon atoms are taken together to form an optionally substitutedbridged bicyclic ring with Ring B.

As defined generally above, the R^(z) group of formula I is —R, —CN,—NO₂, halogen, —C(O)N(R)₂, —C(O)OR, —C(O)R, —N(R)₂, —N(R)C(O)OR,—N(R)C(O)N(R)₂, —OR, or —S(O)₂N(R)₂. In some embodiments, R^(z) ishydrogen. In other embodiments, R^(z) is CN, halogen, —N(R)₂ or—C(O)N(R)₂. Exemplary R^(z) groups include those depicted in Table 1.

As defined generally above, p is 0-2. In some embodiments p is 0. Insome embodiments p is 1. In certain embodiments, p is 2.

In some embodiments, the compound of formula I is not selected from thefollowing compounds:

In certain embodiments, the present invention provides a compound offormula I, wherein Ring B is a benzo fused ring, thereby forming acompound of formula II:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,L¹, L², R^(z), R¹, R⁴, W, m, n, and p is as defined above and describedin embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula II, wherein R¹ is one of the following formulas:

thereby forming a compound of formula II-a or II-b:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,L¹, L², R^(z), R⁴, W, m, n, and p is as defined above and described inembodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula II, wherein m is 1, and -L²(R⁴)_(p)—R⁴ is connected para to Q,thereby forming a compound of formula III:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,L¹, L², R^(z), R¹, R⁴, W, n, and p is as defined above and described inembodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula III, wherein Ring A is cyclohexyl, thereby forming a compound offormula IV:

or a pharmaceutically acceptable salt thereof, wherein each of L¹, L²,R^(z), R¹, R⁴, W, n, and p is as defined above and described inembodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula IV, wherein n is 1 and the cyclohexyl ring has transstereochemistry, thereby forming a compound of formula V:

or a pharmaceutically acceptable salt thereof, wherein each of L¹, L²,R^(z), R¹, R⁴, W, and p is as defined above and described in embodimentsherein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula III, wherein R^(z) is hydrogen, and L² is C₁ alkylene, therebyforming a compound of formula VI:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,L¹, R¹, R⁴, W, n, and p is as defined above and described in embodimentsherein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula III, wherein L² is a covalent bond, thereby forming a compoundof formula VII:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,L¹, R¹, R⁴, W, and n is as defined above and described in embodimentsherein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula I, wherein Ring B is a 6 membered heteroaromatic fused ring,wherein each V is independently C or N, provided that only 1-2 V aresimultaneously N, thereby forming a compound of formula VIII:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,L¹, L², R^(z), R¹, R⁴, W, m, n, and p is as defined above and describedin embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula VIII or a pharmaceutically acceptable salt thereof, wherein oneor more V is C or S substituted with one or more oxo, thiono, or iminogroups.

In certain embodiments, the present invention provides a compound offormula I, wherein Ring B is a 5 membered heteroaryl fused ring, whereineach J is independently C, N, O, or S, provided that only 1-2 J aresimultaneously N, O, or S, thereby forming a compound of formula IX:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,L¹, L², R^(z), R¹, R⁴, W, m, n, and p is as defined above and describedin embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula IX or a pharmaceutically acceptable salt thereof, wherein one ormore J is C or S substituted with one or more oxo, thiono, or iminogroups.

In certain embodiments, the present invention provides a compound offormula I, wherein L¹ is —O—, thereby forming a compound of formula X:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,Ring B, L², R^(z), R¹, R⁴, W, m, n, and p is as defined above anddescribed in embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula X, wherein Ring A is cyclohexyl, thereby forming a compound offormula XI:

or a pharmaceutically acceptable salt thereof, wherein each of Ring B,L², R^(z), R¹, R⁴, W, m, n, and p is as defined above and described inembodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula XI, wherein n is 1 and the cyclohexyl ring has transstereochemistry, thereby forming a compound of formula XII:

or a pharmaceutically acceptable salt thereof, wherein each of Ring B,L², R^(z), R¹, R⁴, W, m, and p is as defined above and described inembodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula I, wherein L¹ is —NR—, thereby forming a compound of formulaXIII:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,Ring B, L², R, R^(z), R¹, R⁴, W, m, n, and p is as defined above anddescribed in embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula XIII, wherein Ring A is cyclohexyl, thereby forming a compoundof formula XIV:

or a pharmaceutically acceptable salt thereof, wherein each of Ring B,L², R, R^(z), R¹, R⁴, W, m, n, and p is as defined above and describedin embodiments herein, both singly and in combination.

In certain embodiments, the present invention provides a compound offormula XIV, wherein n is 1 and the cyclohexyl ring has transstereochemistry, thereby forming a compound of formula XV:

or a pharmaceutically acceptable salt thereof, wherein each of Ring B,L², R, R^(z), R¹, R⁴, W, m, and p is as defined above and described inembodiments herein, both singly and in combination.

Exemplary compounds are set forth in Table 1, below.

TABLE 1 Exemplary Compounds

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

In some embodiments, the present invention provides a compound set forthin Table 1, above, or a pharmaceutically acceptable salt thereof.

Without wishing to be bound by any particular theory, it is believedthat proximity of an inhibitor compound, or pendant moiety of aninhibitor compound, to the water of interest facilitates displacement ordisruption of that water by the inhibitor compound, or pendant moiety ofan inhibitor compound. In some embodiments, a water molecule displacedor disrupted by an inhibitor compound, or pendant moiety of an inhibitorcompound, is an unstable water molecule.

In certain embodiments, the present invention provides a complexcomprising IRAK-4 and an inhibitor, wherein at least one unstable waterof IRAK-4 is displaced or disrupted by the inhibitor. In someembodiments, at least two unstable waters selected are displaced ordisrupted by the inhibitor.

4. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablederivative thereof and a pharmaceutically acceptable carrier, adjuvant,or vehicle. The amount of compound in compositions of this invention issuch that is effective to measurably inhibit an IRAK protein kinase, ora mutant thereof, in a biological sample or in a patient. In certainembodiments, the amount of compound in compositions of this invention issuch that is effective to measurably inhibit an IRAK protein kinase, ora mutant thereof, in a biological sample or in a patient. In certainembodiments, a composition of this invention is formulated foradministration to a patient in need of such composition. In someembodiments, a composition of this invention is formulated for oraladministration to a patient.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitorily active metabolite or residue thereof.

As used herein, the term “inhibitorily active metabolite or residuethereof” means that a metabolite or residue thereof is also an inhibitorof an IRAK protein kinase, or a mutant thereof.

Compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that may be combinedwith the carrier materials to produce a composition in a single dosageform will vary depending upon the host treated, the particular mode ofadministration. Preferably, provided compositions should be formulatedso that a dosage of between 0.01-100 mg/kg body weight/day of theinhibitor can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

Compounds and compositions described herein are generally useful for theinhibition of kinase activity of one or more enzymes.

Examples of kinases that are inhibited by the compounds and compositionsdescribed herein and against which the methods described herein areuseful include those of the interleukin-1 receptor-associated kinase(IRAK) family of kinases, the members of which include IRAK-1, IRAK-2,and IRAK-4, or a mutant thereof. Li et al., “IRAK-4: A novel member ofthe IRAK family with the properties of an IRAK-kinase,” PNAS 2002,99(8), 5567-5572, Flannery et al., “The interleukin-1receptor-associated kinases: Critical regulators of innate immunesignaling” Biochem Pharm 2010, 80(12), 1981-1991 incorporated byreference in its entirety.

The activity of a compound utilized in this invention as an inhibitor ofIRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof, may be assayed invitro, in vivo or in a cell line. In vitro assays include assays thatdetermine inhibition of either the phosphorylation activity and/or thesubsequent functional consequences, or ATPase activity of activatedIRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof. Alternate in vitroassays quantitate the ability of the inhibitor to bind to IRAK-1, IRAK-2and/or IRAK-4. Inhibitor binding may be measured by radiolabeling theinhibitor prior to binding, isolating the inhibitor/IRAK-1,inhibitor/IRAK-2, or inhibitor/IRAK-4 complex and determining the amountof radiolabel bound. Alternatively, inhibitor binding may be determinedby running a competition experiment where new inhibitors are incubatedwith IRAK-1, IRAK-2, and/or IRAK-4 bound to known radioligands.Representative in vitro and in vivo assays useful in assaying an IRAK-4inhibitor include those described and disclosed in, e.g., Kim et al., “Acritical role for IRAK4 kinase activity in Toll-like receptor-mediatedinnate immunity,” J. Exp. Med. 2007 204(5), 1025-1036; Lebakken et al.,“A Fluorescence Lifetime Based Binding Assay to Characterize KinaseInhibitors,” J. Biomol. Screen. 2007, 12(6), 828-841; Maschera et al.,“Overexpression of an enzymatically inactiveinterleukin-1-receptor-associated kinase activates nuclear factor-κB,”Biochem. J. 1999, 339, 227-231; Song et al., “The kinase activities ofinterleukin-e receptor associated kinase (IRAK)-1 and 4 are redundant inthe control of inflammatory cytokine expression in human cells,” Mol.Immunol. 2009, 46, 1458-1466, each of which is herein incorporated byreference in its entirety. Detailed conditions for assaying a compoundutilized in this invention as an inhibitor of IRAK-1, IRAK-2, and/orIRAK-4, or a mutant thereof, are set forth in the Examples below.

The best characterized member of the IRAK family is the serine/threoninekinase IRAK-4. IRAK-4 is implicated in signaling innate immune responsesfrom Toll-like receptors (TLRs) and Toll/IL-1 receptors (TIRs).

Innate immunity detects pathogens through the recognition ofpathogen-associated molecular patterns by TLRs, when then links to theadaptive immune response. TLRs recognize conserved structures of bothmicrobes and endogenous molecules. TLRs which recognize bacterial andfungal components are located on the cell surface, whereas TLRs whichrecognize viral or microbial nucleic acids are localized tointracellular membranes such as endosomes and phagosomes. Cell surfaceTLRs can be targeted by small molecules and antibodies, whereasintracellular TLRs require targeting with oligonucleotides.

TLRs mediate the innate immune response by upregulating the expressionof inflammatory genes in multiple target cells. See, e.g., Sen et al.,“Transcriptional signaling by double-stranded RNA: role of TLR3,”Cytokine & Growth Factor Rev. 2005, 16, 1-14, incorporated by referencein its entirety. While TLR-mediated inflammatory response is criticalfor innate immunity and host defense against infections, uncontrolledinflammation is detrimental to the host leading to sepsis and chronicinflammatory diseases, such as chronic arthritis, atherosclerosis,multiple sclerosis, cancers, autoimmune disorders such as rheumatoidarthritis, lupus, asthma, psoriasis, and inflammatory bowel diseases.

Upon binding of a ligand, most TLRs recruit the adaptor molecule MYD88through the TIR domain, mediating the MYD88-dependent pathway. MYD88then recruits IRAK-4, which engages with the nuclear factor-κB (NF-κB),mitogen-activated protein (MAP) kinase and interferon-regulatory factorcascades and leads to the induction of pro-inflammatory cytokines Theactivation of NF-κB results in the induction of inflammatory cytokinesand chemokines, such as TNF-α, IL-1α, IL-6 and IL-8. The kinase activityof IRAK-4 has been shown to play a critical role in the TLR-mediatedimmune and inflammatory responses. IRAK4 is a key mediator of the innateimmune response orchestrated by interleukin-1 receptor (IL-1R),interleukin-18 receptor (IL-18R), IL-33 receptor (IL-33R), and Toll-likereceptors (TLRs). Inactivation of IRAK-1 and/or IRAK-4 activity has beenshown to result in diminished production of cytokines and chemokines inresponse to stimulation of IL-1 and TLR ligands. See, e.g., Picard etal., “Clinical features and outcome of patients with IRAK-4 and MYD88deficiency,” Medicine (Baltimore), 2010, 89(6), 043-25; Li, “IRAK4 inTLR/IL-1R signaling: Possible clinical applications,” Eur. J. Immunology2008, 38:614-618; Cohen et al., “Targeting protein kinases for thedevelopment of anti-inflammatory drugs,” Curr. Opin. Cell Bio. 2009,21:317-324; Flannery et al., “The interleukin-1 receptor-associatedkinases: Critical regulators of innate immune signalling,” Biochem.Pharm. 2010, 80(12), 1981-1991; Gottipati et al., “IRAK1: A criticalsignaling mediator of innate immunity,” Cellular Signaling 2008, 20,269-276; Kim et al., “A critical role for IRAK4 kinase activity inToll-like receptor-mediated innate immunity,” J. Exp. Med. 2007 204(5),1025-1036; Koziczak-Holbro et al., “IRAK-4 Kinase Activity Is Requiredfor Interleukin-1 (IL-1) Receptor- and Toll-like Receptor 7-mediatedSignaling and Gene Expression,” J. Biol. Chem. 2007, 282(18),13552-13560; Kubo-Murai et al., “IRAK-4-dependent Degradation of IRAK-1is a Negative Feedback Signal for TLR-mediated NF-κB Activation,” J.Biochem. 2008, 143, 295-302; Maschera et al., “Overexpression of anenzymatically inactive interleukin-1-receptor-associated kinaseactivates nuclear factor-κB,” Biochem. J. 1999, 339, 227-231; Lin etal., “Helical assembly in the MYD88-IRAK4-IRAK2 complex in TLR/IL-1Rsignalling,” Nature 2010, 465(17), 885-891; Suzuki et al., “IRAK-4 asthe central TIR signaling mediator in innate immunity,” TRENDS inImmunol. 2002, 23(10), 503-506; Suzuki et al., “Severe impairment ofinterleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4,”Nature 2002, 416, 750-754; Swantek et al., “IL-1 Receptor-AssociatedKinase Modulates Host Responsiveness to Endotoxin,” J. Immunol. 2000,164, 4301-4306; Hennessy, E., et al., “Targeting Toll-like receptors:emerging therapeutics?” Nature Reviews, vol. 9, pp: 293-307 (2010);Dinarello, C. “Interleukin-18 and the Pathogenesis of InflammatoryDiseases,” Seminars in Nephrology, vol. 27, no. 1, pp: 98-114 (2007),each of which is herein incorporated by reference in its entirety. Infact, knockdown mice that express a catalytically inactive mutant IRAK-4protein are completely resistant to septic shock and show impaired IL-1activity. Moreover, these mice are resistant to joint and boneinflammation/destruction in an arthritis model, suggesting that IRAK-4may be targeted to treat chronic inflammation. Further, while IRAK-4appears to be vital for childhood immunity against some pyogenicbacteria, it has been shown to play a redundant role in protectiveimmunity to most infections in adults, as demonstrated by one study inwhich patients older than 14 lacking IRAK-4 activity exhibited noinvasive infections. Cohen et al., “Targeting protein kinases for thedevelopment of anti-inflammatory drugs,” Curr. Opin. Cell Bio. 2009,21:317-324; Ku et al., “Selective predisposition to bacterial infectionsin IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwiseredundant in protective immunity,” J. Exp. Med. 2007, 204(10),2407-2422; Picard et al., “Inherited human IRAK-4 deficiency: anupdate,” Immunol. Res. 2007, 38, 347-352; Song et al., “The kinaseactivities of interleukin-e receptor associated kinase (IRAK)-1 and 4are redundant in the control of inflammatory cytokine expression inhuman cells,” Mol. Immunol. 2009, 46, 1458-1466; Rokosz, L. et al.,“Kinase inhibitors as drugs for chronic inflammatory and immunologicaldiseases: progress and challenges,” Expert Opinions on TherapeuticTargets, 12(7), pp: 883-903 (2008); Gearing, A. “Targeting toll-likereceptors for drug development: a summary of commercial approaches,”Immunology and Cell Biology, 85, pp: 490-494 (2007); Dinarello, C.“IL-1: Discoveries, controversies and future directions,” EuropeanJournal of Immunology, 40, pp: 595-653 (2010), each of which is hereinincorporated by reference in its entirety. Because TLR activationtriggers IRAK-4 kinase activity, IRAK-4 inhibition presents anattractive target for treating the underlying causes of inflammation incountless diseases.

Representative IRAK-4 inhibitors include those described and disclosedin e.g., Buckley et al., Bioorg. Med. Chem. Lett. 2008, 18, 3211-3214;Buckley et al., Bioorg. Med. Chem. Lett. 2008, 18, 3291-3295; Buckley etal., Bioorg. Med. Chem. Lett. 2008, 18, 3656-3660; Powers et al.,“Discovery and initial SAR of inhibitors of interleukin-1receptor-associated kinase-4,” Bioorg. Med. Chem. Lett. 2006, 16,2842-2845; Wng et al., “IRAK-4 Inhibitors for Inflammation,” Curr.Topics in Med. Chem. 2009, 9, 724-737, each of which is hereinincorporated by reference in its entirety.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

Provided compounds are inhibitors of one of more of IRAK-1, IRAK-2,and/or IRAK-4 and are therefore useful for treating one or moredisorders associated with activity of one or more of IRAK-1, IRAK-2,and/or IRAK-4. Thus, in certain embodiments, the present inventionprovides a method for treating a IRAK-1-mediated, a IRAK-2-mediated,and/or a IRAK-4-mediated disorder comprising the step of administeringto a patient in need thereof a compound of the present invention, orpharmaceutically acceptable composition thereof.

As used herein, the terms “IRAK-1-mediated”, “IRAK-2-mediated”, and/or“IRAK-4-mediated” disorders, diseases, and/or conditions as used hereinmeans any disease or other deleterious condition in which one or more ofIRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof, are known to play arole. Accordingly, another embodiment of the present invention relatesto treating or lessening the severity of one or more diseases in whichone or more of IRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof, areknown to play a role.

In some embodiments, the present invention provides a method fortreating one or more disorders, diseases, and/or conditions wherein thedisorder, disease, or condition is a cancer, a neurodegenative disorder,a viral disease, an autoimmune disease, an inflammatory disorder, ahereditary disorder, a hormone-related disease, a metabolic disorder,conditions associated with organ transplantation, immunodeficiencydisorders, a destructive bone disorder, a proliferative disorder, aninfectious disease, a condition associated with cell death,thrombin-induced platelet aggregation, liver disease, pathologic immuneconditions involving T cell activation, a cardiovascular disorder, or aCNS disorder.

Diseases and conditions treatable according to the methods of thisinvention include, but are not limited to, cancer (see, e.g., Ngo, V. etal., “Oncogenically active MYD88 mutations in human lymphoma,” Nature,vol. 000, pp: 1-7 (2010); Lust, J. et al., “Induction of a ChronicDisease State in patients With Smoldering of Indolent Multiple Myelomaby Targeting Interleukin 1β-Induced Interleukin 6 Production and theMyeloma Proliferative Component,” Mayo Clinic Proceedings, 84(2), pp:114-122 (2009)), diabetes, cardiovascular disease, viral disease,autoimmune diseases such as lupus (see, e.g., Dinarello, C.“Interleukin-18 and the Pathogenesis of Inflammatory Diseases,” Seminarsin Nephrology, vol. 27, no. 1, pp: 98-114 (2007); Cohen et al.,“Targeting protein kinases for the development of anti-inflammatorydrugs,” Curr. Opin. Cell Bio. 2009, 21:317-324) and rheumatoid arthritis(see, e.g., Geyer, M. et al., “Actual status of antiinterleukin-1therapies in rheumatic diseases,” Current Opinion in Rheumatology, 22,pp: 246-251 (2010)), autoinflammatory syndromes (see, e.g., Hoffman, H.et al., “Efficacy and Safety of Rilonacept (Interleukin-1 Trap) inPatients with Cryopyrin-Associated Periodic Syndromes,” Arthritis &Rheumatism, vol. 58, no. 8, pp: 2443-2452 (2008)), atherosclerosis,psoriasis, allergic disorders, inflammatory bowel disease (see, e.g.,Cario, E. “Therapeutic Impact of Toll-like Receptors on InflammatoryBowel Diseases: A Multiple-edged Sword,” Inflamm. Bowel Dis., 14, pp:411-421 (2008)), inflammation (see, e.g., Dinarello, C. “Interleukin 1and interleukin 18 as mediators of inflammation and the aging process,”The American Journal of Clinical Nutrition, 83, pp: 447S-455S (2006)),acute and chronic gout and gouty arthritis (see, e.g., Terkeltaub, R.“Update on gout: new therapeutic strategies and options,” Nature, vol.6, pp: 30-38 (2010); Weaver, A. “Epidemiology of gout,” Cleveland ClinicJournal of Medicine, vol. 75, suppl. 5, pp: S9-512 (2008); Dalbeth, N.et al., “Hyperuricaemia and gout: state of the art and futureperspectives,” Annals of Rheumatic Diseases, 69, pp: 1738-1743 (2010);Martinon, F. et al., “Gout-associated uric acid crystals activate theNALP3 inflammasome,” Nature, vol. 440, pp: 237-241 (2006); So, A. etal., “A pilot study of IL-1 inhibition by anakinra in acute gout,”Arthritis Research & Therapy, vol. 9, no. 2, pp: 1-6 (2007); Terkeltaub,R. et al., “The interleukin 1 inhibitor rilonacept in treatment ofchronic gouty arthritis: results of a placebo-controlled, monosequencecrossover, non-randomised, single-blind pilot study,” Annals ofRheumatic Diseases, 68, pp: 1613-1617 (2009); Torres, R. et al.,“Hyperalgesia, synovitis and multiple biomarkers of inflammation aresuppressed by interleukin 1 inhibition in a novel animal model of goutyarthritis,” Annals of Rheumatic Diseases, 68, pp: 1602-1608 (2009)),neurological disorders, metabolic syndrome (see, e.g., Troseid, M. “Therole of interleukin-18 in the metabolic syndrome,” CardiovascularDiabetology, 9:11, pp: 1-8 (2010)), immunodeficiency disorders such asAIDS and HIV (see, e.g., Iannello, A. et al., “Role of Interleukin-18 inthe Development and Pathogenesis of AIDS,” AIDS Reviews, 11, pp: 115-125(2009)), destructive bone disorders (see, e.g., Hennessy, E., et al.,“Targeting Toll-like receptors: emerging therapeutics?” Nature Reviews,vol. 9, pp: 293-307 (2010)), osteoarthritis, proliferative disorders,Waldenström's Macroglobulinemia (see, e.g., Treon, et al., “Whole genomesequencing reveals a widely expressed mutation (MYD88 L265P) withoncogenic activity in Waldenström's Macroglobulinemia” 53^(rd) ASHAnnual Meeting; Xu, et al., “A somatic variant in MYD88 (L256P) revealedby whole genome sequencing differentiates lymphoplasmacytic lymphomafrom marginal zone lymphomas” 53^(rd) ASH Annual Meeting; Yang et al.,“Disruption of MYD88 pathway signaling leads to loss of constitutiveIRAK1, NK-kB and JAK/STAT signaling and induces apoptosis of cellsexpressing the MYD88 L265P mutation in Waldenström's Macroglobulinemia”53^(rd) ASH Annual Meeting; Iriyama et al., “Clinical significance ofgenetic mutations of CD79B, CARD11, MYD88, and EZH2 genes in diffuselarge B-cell lymphoma patients” 53^(rd) ASH Annual Meeting; infectiousdiseases, conditions associated with cell death, pathologic immuneconditions involving T cell activation, and CNS disorders in a patient.In one embodiment, a human patient is treated with a compound of thecurrent invention and a pharmaceutically acceptable carrier, adjuvant,or vehicle, wherein said compound is present in an amount to measurablyinhibit IRAK-1 only, IRAK-2-only, IRAK-4-only and/or IRAK1- and IRAK4kinase activity.

Compounds of the current invention are useful in the treatment of aproliferative disease selected from a benign or malignant tumor, solidtumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder,breast, stomach, gastric tumors, ovaries, colon, rectum, prostate,pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus,larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas,multiple myeloma, gastrointestinal cancer, especially colon carcinoma orcolorectal adenoma, a tumor of the neck and head, an epidermalhyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, aneoplasia of epithelial character, adenoma, adenocarcinoma,keratoacanthoma, epidermoid carcinoma, large cell carcinoma,non-small-cell lung carcinoma, lymphomas, Hodgkins and Non-Hodgkins, amammary carcinoma, follicular carcinoma, undifferentiated carcinoma,papillary carcinoma, seminoma, melanoma, an IL-1 driven disorder, anMYD88 driven disorder, Smoldering of indolent multiple myeloma, orhematological malignancies (including leukemia, diffuse large B-celllymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chroniclymphocytic lymphoma, primary effusion lymphoma, Burkittlymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocyticleukemia, lymphoplasmacytic lymphoma, Waldenström's macroglobulinemia(WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma,intravascular large B-cell lymphoma).

In some embodiments the proliferative disease which can be treatedaccording to the methods of this invention is an MYD88 driven disorder.In some embodiments, the MYD88 driven disorder which can be treatedaccording to the methods of this invention is selected from ABC DLBCL,Waldenström's macroglobulinemia, Hodgkin's lymphoma, primary cutaneousT-cell lymphoma and chronic lymphocytic leukemia.

In some embodiments the proliferative disease which can be treatedaccording to the methods of this invention is an IL-1 driven disorder.In some embodiments the IL-1 driven disorder is Smoldering of indolentmultiple myeloma.

Compounds according to the invention are useful in the treatment ofinflammatory or obstructive airways diseases, resulting, for example, inreduction of tissue damage, airways inflammation, bronchialhyperreactivity, remodeling or disease progression. Inflammatory orobstructive airways diseases to which the present invention isapplicable include asthma of whatever type or genesis including bothintrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mildasthma, moderate asthma, severe asthma, bronchitic asthma,exercise-induced asthma, occupational asthma and asthma inducedfollowing bacterial infection. Treatment of asthma is also to beunderstood as embracing treatment of subjects, e.g. of less than 4 or 5years of age, exhibiting wheezing symptoms and diagnosed or diagnosableas “wheezy infants”, an established patient category of major medicalconcern and now often identified as incipient or early-phase asthmatics.

Compounds according to the invention are useful in the treatment ofheteroimmune diseases. Examples of such heteroimmune diseases include,but are not limited to, graft versus host disease, transplantation,transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens,latex, drugs, foods, insect poisons, animal hair, animal dander, dustmites, or cockroach calyx), type I hypersensitivity, allergicconjunctivitis, allergic rhinitis, and atopic dermatitis.

Prophylactic efficacy in the treatment of asthma will be evidenced byreduced frequency or severity of symptomatic attack, e.g. of acuteasthmatic or bronchoconstrictor attack, improvement in lung function orimproved airways hyperreactivity. It may further be evidenced by reducedrequirement for other, symptomatic therapy, such as therapy for orintended to restrict or abort symptomatic attack when it occurs, forexample antiinflammatory or bronchodilatory. Prophylactic benefit inasthma may in particular be apparent in subjects prone to “morningdipping”. “Morning dipping” is a recognized asthmatic syndrome, commonto a substantial percentage of asthmatics and characterised by asthmaattack, e.g. between the hours of about 4 to 6 am, i.e. at a timenormally substantially distant form any previously administeredsymptomatic asthma therapy.

Compounds of the current invention can be used for other inflammatory orobstructive airways diseases and conditions to which the presentinvention is applicable and include acute lung injury (ALI), adult/acuterespiratory distress syndrome (ARDS), chronic obstructive pulmonary,airways or lung disease (COPD, COAD or COLD), including chronicbronchitis or dyspnea associated therewith, emphysema, as well asexacerbation of airways hyperreactivity consequent to other drugtherapy, in particular other inhaled drug therapy. The invention is alsoapplicable to the treatment of bronchitis of whatever type or genesisincluding, but not limited to, acute, arachidic, catarrhal, croupus,chronic or phthinoid bronchitis. Further inflammatory or obstructiveairways diseases to which the present invention is applicable includepneumoconiosis (an inflammatory, commonly occupational, disease of thelungs, frequently accompanied by airways obstruction, whether chronic oracute, and occasioned by repeated inhalation of dusts) of whatever typeor genesis, including, for example, aluminosis, anthracosis, asbestosis,chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.

With regard to their anti-inflammatory activity, in particular inrelation to inhibition of eosinophil activation, compounds of theinvention are also useful in the treatment of eosinophil relateddisorders, e.g. eosinophilia, in particular eosinophil related disordersof the airways (e.g. involving morbid eosinophilic infiltration ofpulmonary tissues) including hypereosinophilia as it effects the airwaysand/or lungs as well as, for example, eosinophil-related disorders ofthe airways consequential or concomitant to Loffler's syndrome,eosinophilic pneumonia, parasitic (in particular metazoan) infestation(including tropical eosinophilia), bronchopulmonary aspergillosis,polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilicgranuloma and eosinophil-related disorders affecting the airwaysoccasioned by drug-reaction.

Compounds of the invention are also useful in the treatment ofinflammatory or allergic conditions of the skin, for example psoriasis,contact dermatitis, atopic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiformis, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, lupuserythematosus, systemic lupus erythematosus, pemphigus vulgaris,pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosaacquisita, acne vulgaris, and other inflammatory or allergic conditionsof the skin.

Compounds of the invention may also be used for the treatment of otherdiseases or conditions, such as diseases or conditions having aninflammatory component, for example, treatment of diseases andconditions of the eye such as ocular allergy, conjunctivitis,keratoconjunctivitis sicca, and vernal conjunctivitis, diseasesaffecting the nose including allergic rhinitis, and inflammatory diseasein which autoimmune reactions are implicated or having an autoimmunecomponent or etiology, including autoimmune hematological disorders(e.g. hemolytic anemia, aplastic anemia, pure red cell anemia andidiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoidarthritis, polychondritis, scleroderma, Wegener granulamatosis,dermatomyositis, chronic active hepatitis, myasthenia gravis,Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory boweldisease (e.g. ulcerative colitis and Crohn's disease), irritable bowelsyndrome, celiac disease, periodontitis, hyaline membrane disease,kidney disease, glomerular disease, alcoholic liver disease, multiplesclerosis, endocrine ophthalmopathy, Grave's disease, sarcoidosis,alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis,primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren'ssyndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis,interstitial lung fibrosis, psoriatic arthritis, systemic juvenileidiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis,vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis(with and without nephrotic syndrome, e.g. including idiopathicnephrotic syndrome or minal change nephropathy), chronic granulomatousdisease, endometriosis, leptospiriosis renal disease, glaucoma, retinaldisease, ageing, headache, pain, complex regional pain syndrome, cardiachypertrophy, musclewasting, catabolic disorders, obesity, fetal growthretardation, hypercholesterolemia, heart disease, chronic heart failure,mesothelioma, anhidrotic ecodermal dysplasia, Behcet's disease,incontinentia pigmenti, Paget's disease, pancreatitis, hereditaryperiodic fever syndrome, asthma (allergic and non-allergic, mild,moderate, severe, bronchitic, and exercise-induced), acute lung injury,acute respiratory distress syndrome, eosinophilia, hypersensitivities,anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases,COPD (reduction of damage, airways inflammation, bronchialhyperreactivity, remodeling or disease progression), pulmonary disease,cystic fibrosis, acid-induced lung injury, pulmonary hypertension,polyneuropathy, cataracts, muscle inflammation in conjunction withsystemic sclerosis, inclusion body myositis, myasthenia gravis,thyroiditis, Addison's disease, lichen planus, Type 1 diabetes, or Type2 diabetes, appendicitis, atopic dermatitis, asthma, allergy,blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,cholangitis, cholecystitis, chronic graft rejection, colitis,conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis,dermatomyositis, encephalitis, endocarditis, endometritis, enteritis,enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis,gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis,hidradenitis suppurativa, immunoglobulin A nephropathy, interstitiallung disease, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis,prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis,uveitis, vaginitis, vasculitis, or vulvitis.

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is an disease of the skin. Insome embodiments, the inflammatory disease of the skin is selected fromcontact dermatitis, atompic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiformis, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigusvulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysisbullosa acquisita, and other inflammatory or allergic conditions of theskin.

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is selected from acute andchronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis,rheumatoid arthritis, Juvenile rheumatoid arthritis, Systemic jubenileidiopathic arthritis (SJIA), Cryopyrin Associated Periodic Syndrome(CAPS), and osteoarthritis.

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is a TH17 mediated disease.In some embodiments the TH17 mediated disease is selected from Systemiclupus erythematosus, Multiple sclerosis, and inflammatory bowel disease(including Crohn's disease or ulcerative colitis).

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is selected from Sjogren'ssyndrome, allergic disorders, osteoarthritis, conditions of the eye suchas ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernalconjunctivitis, and diseases affecting the nose such as allergicrhinitis.

Cardiovascular diseases which can be treated according to the methods ofthis invention include, but are not limited to, restenosis,cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke,congestive heart failure, angina pectoris, reocclusion afterangioplasty, restenosis after angioplasty, reocclusion afteraortocoronary bypass, restenosis after aortocoronary bypass, stroke,transitory ischemia, a peripheral arterial occlusive disorder, pulmonaryembolism, and deep venous thrombosis.

In some embodiments, the neurodegenerative disease which can be treatedaccording to the methods of this invention include, but are not limitedto, Alzheimer's disease, Parkinson's disease, amyotrophic lateralsclerosis, Huntington's disease, cerebral ischemia, andneurodegenerative disease caused by traumatic injury, glutamateneurotoxicity, hypoxia, epilepsy, treatment of diabetes, metabolicsyndrome, obesity, organ transplantation and graft versus host disease.

In some embodiments the invention provides a method of treating adisease or condition commonly occurring in connection withtransplantation. In some embodiments, the disease or condition commonlyoccurring in connection with transplantation is selected from organtransplantation, organ transplant rejection, and graft versus hostdisease.

In some embodiments the invention provides a method of treating ametabolic disease. In some embodiments the metabolic disease is selectedfrom Type 1 diabetes, Type 2 diabetes, metabolic syndrome, and obesity.

In some embodiments the invention provides a method of treating a viraldisease. In some embodiments, the viral infection is HIV infection.

Furthermore, the invention provides the use of a compound according tothe definitions herein, or a pharmaceutically acceptable salt, or ahydrate or solvate thereof for the preparation of a medicament for thetreatment of a proliferative disease, an inflammatory disease, anobstructive respiratory disease, a cardiovascular disease, a metabolicdisease, a neurological disease, a neurodegenerative disease, a viraldisease, or a disorder commonly occurring in connection withtransplantation.

Combination Therapies

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents, which are normally administered to treatthat condition, may be administered in combination with compounds andcompositions of this invention. As used herein, additional therapeuticagents that are normally administered to treat a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated.”

In certain embodiments, a provided combination, or composition thereof,is administered in combination with another therapeutic agent.

Examples of agents the combinations of this invention may also becombined with include, without limitation: treatments for Alzheimer'sDisease such as Aricept® and Excelon®; treatments for HIV such asritonavir; treatments for Parkinson's Disease such as L-DOPA/carbidopa,entacapone, ropinrole, pramipexole, bromocriptine, pergolide,trihexephendyl, and amantadine; agents for treating Multiple Sclerosis(MS) such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, andmitoxantrone; treatments for asthma such as albuterol and Singulair®;agents for treating schizophrenia such as zyprexa, risperdal, seroquel,and haloperidol; anti-inflammatory agents such as corticosteroids, TNFblockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine;immunomodulatory and immunosuppressive agents such as cyclosporin,tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine;neurotrophic factors such as acetylcholinesterase inhibitors, MAOinhibitors, interferons, anti-convulsants, ion channel blockers,riluzole, and anti-Parkinsonian agents; agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins; agents for treatingliver disease such as corticosteroids, cholestyramine, interferons, andanti-viral agents; agents for treating blood disorders such ascorticosteroids, anti-leukemic agents, and growth factors; agents thatprolong or improve pharmacokinetics such as cytochrome P450 inhibitors(i.e., inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e.g.,ketokenozole and ritonavir), and agents for treating immunodeficiencydisorders such as gamma globulin.

In certain embodiments, combination therapies of the present invention,or a pharmaceutically acceptable composition thereof, are administeredin combination with a monoclonal antibody or an siRNA therapeutic.

Those additional agents may be administered separately from a providedcombination therapy, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a combination ofthe present invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

In one embodiment, the present invention provides a compositioncomprising a compound of formula I and one or more additionaltherapeutic agents. The therapeutic agent may be administered togetherwith a compound of formula I, or may be administered prior to orfollowing administration of a compound of formula I. Suitabletherapeutic agents are described in further detail below. In certainembodiments, a compound of formula I may be administered up to 5minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours,12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hoursbefore the therapeutic agent. In other embodiments, a compound offormula I may be administered up to 5 minutes, 10 minutes, 15 minutes,30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14hours, 15 hours, 16 hours, 17 hours, or 18 hours following thetherapeutic agent.

In another embodiment, the present invention provides a method oftreating an inflammatory disease, disorder or condition by administeringto a patient in need thereof a compound of formula I and one or moreadditional therapeutic agents. Such additional therapeutic agents may besmall molecules or recombinant biologic agents and include, for example,acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such asaspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone,methylprednisolone, hydrocortisone, and the like, probenecid,allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®),antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine(Aralen®), methotrexate (Rheumatrex®), gold salts such as goldthioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin(Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine(Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®),cyclosporine (Sandimmune®), leflunomide (Arava®) and “anti-TNF” agentssuch as etanercept (Enbrel®), infliximab (Remicade®), golimumab(Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®),“anti-IL-1” agents such as anakinra (Kineret®) and rilonacept(Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors such astofacitinib, antibodies such as rituximab (Rituxan®), “anti-T-cell”agents such as abatacept (Orencia®), “anti-IL-6” agents such astocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc®or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulantssuch as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®),antidiarrheals such as diphenoxylate (Lomotil®) and loperamide(Imodium®), bile acid binding agents such as cholestyramine, alosetron(Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk ofMagnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® andSenokot®, anticholinergics or antispasmodics such as dicyclomine(Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA,Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®),pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®),salmeterol xinafoate (Serevent®) and formoterol (Foradil®),anticholinergic agents such as ipratropium bromide (Atrovent®) andtiotropium (Spiriva®), inhaled corticosteroids such as beclomethasonedipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide(Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), andflunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium(Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®,Slo-Bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such asomalizumab (Xolair®), nucleoside reverse transcriptase inhibitors suchas zidovudine (Retrovir®), abacavir (Ziagen®), abacavir/lamivudine(Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine(Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®),lamivudine/zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine(Hivid®), non-nucleoside reverse transcriptase inhibitors such asdelavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®)and etravirine (Intelence®), nucleotide reverse transcriptase inhibitorssuch as tenofovir (Viread®), protease inhibitors such as amprenavir(Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®),fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir(Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir(Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitorssuch as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integraseinhibitors such as raltegravir (Isentress®), doxorubicin(Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), anddexamethasone (Decadron®) in combination with lenalidomide (Revlimid®),or any combination(s) thereof.

In another embodiment, the present invention provides a method oftreating gout comprising administering to a patient in need thereof acompound of formula I and one or more additional therapeutic agentsselected from non-steroidal anti-inflammatory drugs (NSAIDS) such asaspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone,methylprednisolone, hydrocortisone, and the like, probenecid,allopurinol and febuxostat (Uloric®).

In another embodiment, the present invention provides a method oftreating rheumatoid arthritis comprising administering to a patient inneed thereof a compound of formula I and one or more additionaltherapeutic agents selected from non-steroidal anti-inflammatory drugs(NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) andcelecoxib, corticosteroids such as prednisone, prednisolone,methylprednisolone, hydrocortisone, and the like, sulfasalazine(Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) andchloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such asgold thioglucose (Solganal®), gold thiomalate (Myochrysine®) andauranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®),azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil(Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and“anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®),golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab(Humira®), “anti-IL-1” agents such as anakinra (Kineret®) and rilonacept(Arcalyst®), antibodies such as rituximab (Rituxan®), “anti-T-cell”agents such as abatacept (Orencia®) and “anti-IL-6” agents such astocilizumab (Actemra®).

In one embodiment, the present invention provides a method of treatingosteoarthritis comprising administering to a patient in need thereof acompound of formula I and one or more additional therapeutic agentsselected from acetaminophen, non-steroidal anti-inflammatory drugs(NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) andcelecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®)and monoclonal antibodies such as tanezumab.

In one embodiment, the present invention provides a method of treatinglupus comprising administering to a patient in need thereof a compoundof formula I and one or more additional therapeutic agents selected fromacetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such asaspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,corticosteroids such as prednisone, prednisolone, methylprednisolone,hydrocortisone, and the like, antimalarials such as hydroxychloroquine(Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®),methotrexate (Rheumatrex®), azathioprine (Imuran®) and anticoagulantssuch as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

In another embodiment, the present invention provides a method oftreating inflammatory bowel disease comprising administering to apatient in need thereof a compound of formula I and one or moreadditional therapeutic agents selected from mesalamine (Asacol®)sulfasalazine (Azulfidine®), antidiarrheals such as diphenoxylate(Lomotil®) and loperamide (Imodium®), bile acid binding agents such ascholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®),laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®),Dulcolax®, Correctol® and Senokot® and anticholinergics orantispasmodics such as dicyclomine (Bentyl®), anti-TNF therapies,steroids, and antibiotics such as Flagyl or ciprofloxacin.

In another embodiment, the present invention provides a method oftreating asthma comprising administering to a patient in need thereof acompound of formula I and one or more additional therapeutic agentsselected from Singulair®, beta-2 agonists such as albuterol (Ventolin®HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol(Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate(Brethaire®), salmeterol xinafoate (Serevent®) and formoterol(Foradil®), anticholinergic agents such as ipratropium bromide(Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such asprednisone, prednisolone, beclomethasone dipropionate (Beclovent®,Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone(Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®,Symbicort®, and Dulera®, cromolyn sodium (Intal®), methylxanthines suchas theophylline (Theo-Dur®, Theolair®, Slo-Bid®, Uniphyl®, Theo-24®) andaminophylline, and IgE antibodies such as omalizumab (Xolair®).

In another embodiment, the present invention provides a method oftreating COPD comprising administering to a patient in need thereof acompound of formula I and one or more additional therapeutic agentsselected from beta-2 agonists such as albuterol (Ventolin® HFA,Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®),pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®),salmeterol xinafoate (Serevent®) and formoterol (Foradil®),anticholinergic agents such as ipratropium bromide (Atrovent®) andtiotropium (Spiriva®), methylxanthines such as theophylline (Theo-Dur®,Theolair®, Slo-Bid®, Uniphyl®, Theo-24®) and aminophylline, inhaledcorticosteroids such as prednisone, prednisolone, beclomethasonedipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide(Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®),flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®,

In another embodiment, the present invention provides a method oftreating HIV comprising administering to a patient in need thereof acompound of formula I and one or more additional therapeutic agentsselected from nucleoside reverse transcriptase inhibitors such aszidovudine (Retrovir®), abacavir (Ziagen®), abacavir/lamivudine(Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine(Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®),lamivudine/zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine(Hivid®), non-nucleoside reverse transcriptase inhibitors such asdelavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®)and etravirine (Intelence®), nucleotide reverse transcriptase inhibitorssuch as tenofovir (Viread®), protease inhibitors such as amprenavir(Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®),fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir(Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir(Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitorssuch as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integraseinhibitors such as raltegravir (Isentress®), and combinations thereof.

In another embodiment, the present invention provides a method oftreating a hematological malignancy comprising administering to apatient in need thereof a compound of formula I and one or moreadditional therapeutic agents selected from rituximab (Rituxan®),cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®),vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, aBTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3Kinhibitor, a SYK inhibitor, and combinations thereof.

In another embodiment, the present invention provides a method oftreating a solid tumor comprising administering to a patient in needthereof a compound of formula I and one or more additional therapeuticagents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®),doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, ahedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor,a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinationsthereof.

In another embodiment, the present invention provides a method oftreating a hematological malignancy comprising administering to apatient in need thereof a compound of formula I and a Hedgehog (Hh)signaling pathway inhibitor. In some embodiments, the hematologicalmalignancy is DLBCL (Ramirez et al “Defining causative factorscontributing in the activation of hedgehog signaling in diffuse largeB-cell lymphoma” Leuk. Res. (2012), published online July 17, andincorporated herein by reference in its entirety).

In another embodiment, the present invention provides a method oftreating diffuse large B-cell lymphoma (DLBCL) comprising administeringto a patient in need thereof a compound of formula I and one or moreadditional therapeutic agents selected from rituximab (Rituxan®),cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®),vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, andcombinations thereof.

In another embodiment, the present invention provides a method oftreating multiple myeloma comprising administering to a patient in needthereof a compound of formula I and one or more additional therapeuticagents selected from bortezomib (Velcade®), and dexamethasone(Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, aJAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYKinhibitor in combination with lenalidomide (Revlimid®).

In another embodiment, the present invention provides a method oftreating Waldenström's macroglobulinemia comprising administering to apatient in need thereof a compound of formula I and one or moreadditional therapeutic agents selected from chlorambucil (Leukeran®),cyclophosphamide (Cytoxan®, Neosar®), fludarabine (Fludara®), cladribine(Leustatin®), rituximab (Rituxan®), a hedgehog signaling inhibitor, aBTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3Kinhibitor, and a SYK inhibitor.

In another embodiment, the present invention provides a method oftreating organ transplant rejection or graft vs. host disease,comprising administering to a patient in need thereof a compound offormula I and one or more additional therapeutic agents selected from asteroid, cyclosporin, FK506, rapamycin, a hedgehog signaling inhibitor,a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3Kinhibitor, and a SYK inhibitor.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a compound of formula I and a BTKinhibitor, wherein the disease is selected from inflammatory boweldisease, arthritis, systemic lupus erythematosus (SLE), vasculitis,idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis,psoriatic arthritis, osteoarthritis, Still's disease, juvenilearthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord'sthyroiditis, Graves' disease, autoimmune thyroiditis, Sjogren'ssyndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis,Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison'sdisease, opsoclonus-myoclonus syndrome, ankylosing spondylosis,antiphospholipid antibody syndrome, aplastic anemia, autoimmunehepatitis, autoimmune gastritis, pernicious anemia, celiac disease,Goodpasture's syndrome, idiopathic thrombocytopenic purpura, opticneuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome,Takayasu's arteritis, temporal arteritis, warm autoimmune hemolyticanemia, Wegener's granulomatosis, psoriasis, alopecia universalis,Behcet's disease, chronic fatigue, dysautonomia, membranousglomerulonephropathy, endometriosis, interstitial cystitis, pemphigusvulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, ahyperproliferative disease, rejection of transplanted organs or tissues,Acquired Immunodeficiency Syndrome (AIDS, also known as HIV), type 1diabetes, graft versus host disease, transplantation, transfusion,anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs,foods, insect poisons, animal hair, animal dander, dust mites, orcockroach calyx), type I hypersensitivity, allergic conjunctivitis,allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopicdermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis,bursitis, cervicitis, cholangitis, cholecystitis, chronic graftrejection, colitis, conjunctivitis, Crohn's disease, cystitis,dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis,endometritis, enteritis, enterocolitis, epicondylitis, epididymitis,fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonleinpurpura, hepatitis, hidradenitis suppurativa, immunoglobulin Anephropathy, interstitial lung disease, laryngitis, mastitis,meningitis, myelitis myocarditis, myositis, nephritis, oophoritis,orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis,peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia,polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis,salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis,ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, B-cellproliferative disorder, e.g., diffuse large B cell lymphoma, follicularlymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia,acute lymphocytic leukemia, B-cell prolymphocytic leukemia,lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenicmarginal zone lymphoma, multiple myeloma (also known as plasma cellmyeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma,extranodal marginal zone B cell lymphoma, nodal marginal zone B celllymphoma, mantle cell lymphoma, mediastinal (thymic) large B celllymphoma, intravascular large B cell lymphoma, primary effusionlymphoma, Burkitt lymphoma/leukemia, or lymphomatoid granulomatosis,breast cancer, prostate cancer, or cancer of the mast cells (e.g.,mastocytoma, mast cell leukemia, mast cell sarcoma, systemicmastocytosis), bone cancer, colorectal cancer, pancreatic cancer,diseases of the bone and joints including, without limitation,rheumatoid arthritis, seronegative spondyloarthropathies (includingankylosing spondylitis, psoriatic arthritis and Reiter's disease),Behcet's disease, Sjogren's syndrome, systemic sclerosis, osteoporosis,bone cancer, bone metastasis, a thromboembolic disorder, (e.g.,myocardial infarct, angina pectoris, reocclusion after angioplasty,restenosis after angioplasty, reocclusion after aortocoronary bypass,restenosis after aortocoronary bypass, stroke, transitory ischemia, aperipheral arterial occlusive disorder, pulmonary embolism, deep venousthrombosis), inflammatory pelvic disease, urethritis, skin sunburn,sinusitis, pneumonitis, encephalitis, meningitis, myocarditis,nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis,dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitus,agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowelsyndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection,hyperacute rejection of transplanted organs, asthma, allergic rhinitis,chronic obstructive pulmonary disease (COPD), autoimmune polyglandulardisease (also known as autoimmune polyglandular syndrome), autoimmunealopecia, pernicious anemia, glomerulonephritis, dermatomyositis,multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic andthrombocytopenic states, Goodpasture's syndrome, atherosclerosis,Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes,septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis,psoriatic arthritis, juvenile arthritis, osteoarthritis, chronicidiopathic thrombocytopenic purpura, Waldenstrom macroglobulinemia,myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis,degenerative joint disease, vitiligo, autoimmune hypopituitarism,Guillain-Barre syndrome, Behcet's disease, scleraderma, mycosisfungoides, acute inflammatory responses (such as acute respiratorydistress syndrome and ischemia/reperfusion injury), and Graves' disease.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a compound of formula I and a PI3Kinhibitor, wherein the disease is selected from a cancer, aneurodegenative disorder, an angiogenic disorder, a viral disease, anautoimmune disease, an inflammatory disorder, a hormone-related disease,conditions associated with organ transplantation, immunodeficiencydisorders, a destructive bone disorder, a proliferative disorder, aninfectious disease, a condition associated with cell death,thrombin-induced platelet aggregation, chronic myelogenous leukemia(CML), chronic lymphocytic leukemia (CLL), liver disease, pathologicimmune conditions involving T cell activation, a cardiovasculardisorder, and a CNS disorder.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a compound of formula I and a PI3Kinhibitor, wherein the disease is selected from benign or malignanttumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cellcarcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach,gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung,vagina, endometrium, cervix, testis, genitourinary tract, esophagus,larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas,multiple myeloma or gastrointestinal cancer, especially colon carcinomaor colorectal adenoma or a tumor of the neck and head, an epidermalhyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, aneoplasia of epithelial character, adenoma, adenocarcinoma,keratoacanthoma, epidermoid carcinoma, large cell carcinoma,non-small-cell lung carcinoma, lymphomas, (including, for example,non-Hodgkin's Lymphoma (NHL) and Hodgkin's lymphoma (also termedHodgkin's or Hodgkin's disease)), a mammary carcinoma, follicularcarcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma,melanoma, or a leukemia, diseases include Cowden syndrome,Lhermitte-Dudos disease and Bannayan-Zonana syndrome, or diseases inwhich the PI3K/PKB pathway is aberrantly activated, asthma of whatevertype or genesis including both intrinsic (non-allergic) asthma andextrinsic (allergic) asthma, mild asthma, moderate asthma, severeasthma, bronchitic asthma, exercise-induced asthma, occupational asthmaand asthma induced following bacterial infection, acute lung injury(ALI), adult/acute respiratory distress syndrome (ARDS), chronicobstructive pulmonary, airways or lung disease (COPD, COAD or COLD),including chronic bronchitis or dyspnea associated therewith, emphysema,as well as exacerbation of airways hyperreactivity consequent to otherdrug therapy, in particular other inhaled drug therapy, bronchitis ofwhatever type or genesis including, but not limited to, acute,arachidic, catarrhal, croupus, chronic or phthinoid bronchitis,pneumoconiosis (an inflammatory, commonly occupational, disease of thelungs, frequently accompanied by airways obstruction, whether chronic oracute, and occasioned by repeated inhalation of dusts) of whatever typeor genesis, including, for example, aluminosis, anthracosis, asbestosis,chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis,Loffler's syndrome, eosinophilic, pneumonia, parasitic (in particularmetazoan) infestation (including tropical eosinophilia),bronchopulmonary aspergillosis, polyarteritis nodosa (includingChurg-Strauss syndrome), eosinophilic granuloma and eosinophil-relateddisorders affecting the airways occasioned by drug-reaction, psoriasis,contact dermatitis, atopic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiformis, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, lupuserythematosus, pemphisus, epidermolysis bullosa acquisita,conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis,diseases affecting the nose including allergic rhinitis, andinflammatory disease in which autoimmune reactions are implicated orhaving an autoimmune component or etiology, including autoimmunehematological disorders (e.g. hemolytic anemia, aplastic anemia, purered cell anemia and idiopathic thrombocytopenia), systemic lupuserythematosus, rheumatoid arthritis, polychondritis, sclerodoma, Wegenergranulamatosis, dermatomyositis, chronic active hepatitis, myastheniagravis, Steven-Johnson syndrome, idiopathic sprue, autoimmuneinflammatory bowel disease (e.g. ulcerative colitis and Crohn'sdisease), endocrine ophthalmopathy, Grave's disease, sarcoidosis,alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis,primary biliary cirrhosis, uveitis (anterior and posterior),keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitiallung fibrosis, psoriatic arthritis and glomerulonephritis (with andwithout nephrotic syndrome, e.g. including idiopathic nephrotic syndromeor minal change nephropathy, restenosis, cardiomegaly, atherosclerosis,myocardial infarction, ischemic stroke and congestive heart failure,Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,Huntington's disease, and cerebral ischemia, and neurodegenerativedisease caused by traumatic injury, glutamate neurotoxicity and hypoxia.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of acancer, an autoimmune disorder, a proliferative disorder, aninflammatory disorder, a neurodegenerative or neurological disorder,schizophrenia, a bone-related disorder, liver disease, or a cardiacdisorder. The exact amount required will vary from subject to subject,depending on the species, age, and general condition of the subject, theseverity of the infection, the particular agent, its mode ofadministration, and the like. Compounds of the invention are preferablyformulated in dosage unit form for ease of administration and uniformityof dosage. The expression “dosage unit form” as used herein refers to aphysically discrete unit of agent appropriate for the patient to betreated. It will be understood, however, that the total daily usage ofthe compounds and compositions of the present invention will be decidedby the attending physician within the scope of sound medical judgment.The specific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

According to one embodiment, the invention relates to a method ofinhibiting protein kinase activity in a biological sample comprising thestep of contacting said biological sample with a compound of thisinvention, or a composition comprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting IRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof, activityin a biological sample comprising the step of contacting said biologicalsample with a compound of this invention, or a composition comprisingsaid compound. In certain embodiments, the invention relates to a methodof irreversibly inhibiting IRAK-1, IRAK-2, and/or IRAK-4, or a mutantthereof, activity in a biological sample comprising the step ofcontacting said biological sample with a compound of this invention, ora composition comprising said compound.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of protein kinase, or a protein kinase selected from IRAK-1,IRAK-2, and/or IRAK-4, or a mutant thereof, activity in a biologicalsample is useful for a variety of purposes that are known to one ofskill in the art. Examples of such purposes include, but are not limitedto, blood transfusion, organ-transplantation, biological specimenstorage, and biological assays.

Another embodiment of the present invention relates to a method ofinhibiting protein kinase activity in a patient comprising the step ofadministering to said patient a compound of the present invention, or acomposition comprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting one or more of IRAK-1, IRAK-2, and/or IRAK-4, or a mutantthereof, activity in a patient comprising the step of administering tosaid patient a compound of the present invention, or a compositioncomprising said compound. According to certain embodiments, theinvention relates to a method of irreversibly inhibiting one or more ofIRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof, activity in apatient comprising the step of administering to said patient a compoundof the present invention, or a composition comprising said compound. Inother embodiments, the present invention provides a method for treatinga disorder mediated by one or more of IRAK-1, IRAK-2, and/or IRAK-4, ora mutant thereof, in a patient in need thereof, comprising the step ofadministering to said patient a compound according to the presentinvention or pharmaceutically acceptable composition thereof. Suchdisorders are described in detail herein.

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents that are normally administered to treatthat condition, may also be present in the compositions of thisinvention. As used herein, additional therapeutic agents that arenormally administered to treat a particular disease, or condition, areknown as “appropriate for the disease, or condition, being treated.”

A compound of the current invention may also be used to advantage incombination with other antiproliferative compounds. Suchantiproliferative compounds include, but are not limited to aromataseinhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase IIinhibitors; microtubule active compounds; alkylating compounds; histonedeacetylase inhibitors; compounds which induce cell differentiationprocesses; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors;antineoplastic antimetabolites; platin compounds; compoundstargeting/decreasing a protein or lipid kinase activity and furtheranti-angiogenic compounds; compounds which target, decrease or inhibitthe activity of a protein or lipid phosphatase; gonadorelin agonists;anti-androgens; methionine aminopeptidase inhibitors; matrixmetalloproteinase inhibitors; bisphosphonates; biological responsemodifiers; antiproliferative antibodies; heparanase inhibitors;inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasomeinhibitors; compounds used in the treatment of hematologic malignancies;compounds which target, decrease or inhibit the activity of Flt-3; Hsp90inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507),17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin,NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from ConformaTherapeutics; temozolomide (Temodal®); kinesin spindle proteininhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, orpentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such asARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 fromPfizer and leucovorin. The term “aromatase inhibitor” as used hereinrelates to a compound which inhibits estrogen production, for instance,the conversion of the substrates androstenedione and testosterone toestrone and estradiol, respectively. The term includes, but is notlimited to steroids, especially atamestane, exemestane and formestaneand, in particular, non-steroids, especially aminoglutethimide,roglethimide, pyridoglutethimide, trilostane, testolactone,ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestaneis marketed under the trade name Aromasin™. Formestane is marketed underthe trade name Lentaron™. Fadrozole is marketed under the trade nameAfema™. Anastrozole is marketed under the trade name Arimidex™.Letrozole is marketed under the trade names Femara™ or Femar™.Aminoglutethimide is marketed under the trade name Orimeten™. Acombination of the invention comprising a chemotherapeutic agent whichis an aromatase inhibitor is particularly useful for the treatment ofhormone receptor positive tumors, such as breast tumors.

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen is marketed under the trade nameNolvadex™. Raloxifene hydrochloride is marketed under the trade nameEvista™. Fulvestrant can be administered under the trade name Faslodex™.A combination of the invention comprising a chemotherapeutic agent whichis an antiestrogen is particularly useful for the treatment of estrogenreceptor positive tumors, such as breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (Casodex™). The term“gonadorelin agonist” as used herein includes, but is not limited toabarelix, goserelin and goserelin acetate. Goserelin can be administeredunder the trade name Zoladex™.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecin and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148. Irinotecan can be administered, e.g. in the formas it is marketed, e.g. under the trademark Camptosar™. Topotecan ismarketed under the trade name Hycamptin™.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, such as Caelyx™), daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide is marketed under the trade name Etopophos™. Teniposide ismarketed under the trade name VM 26-Bristol Doxorubicin is marketedunder the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketedunder the trade name Farmorubicin™. Idarubicin is marketed. under thetrade name Zavedos™. Mitoxantrone is marketed under the trade nameNovantron.

The term “microtubule active agent” relates to microtubule stabilizing,microtubule destabilizing compounds and microtublin polymerizationinhibitors including, but not limited to taxanes, such as paclitaxel anddocetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate,vincristine or vincristine sulfate, and vinorelbine; discodermolides;colchicine and epothilones and derivatives thereof. Paclitaxel ismarketed under the trade name Taxol™. Docetaxel is marketed under thetrade name Taxotere™. Vinblastine sulfate is marketed under the tradename Vinblastin R.P™. Vincristine sulfate is marketed under the tradename Farmistin™.

The term “alkylating agent” as used herein includes, but is not limitedto, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU orGliadel). Cyclophosphamide is marketed under the trade name Cyclostin™.Ifosfamide is marketed under the trade name Holoxan™.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes, but is not limited to,suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabineis marketed under the trade name Xeloda™. Gemcitabine is marketed underthe trade name Gemzar™.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g. under thetrademark Carboplat™. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark Eloxatin™.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity; or a protein or lipid phosphatase activity; or furtheranti-angiogenic compounds” as used herein includes, but is not limitedto, protein tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, such as a) compounds targeting,decreasing or inhibiting the activity of the platelet-derived growthfactor-receptors (PDGFR), such as compounds which target, decrease orinhibit the activity of PDGFR, especially compounds which inhibit thePDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, suchas imatinib, SU101, SU6668 and GFB-111; b) compounds targeting,decreasing or inhibiting the activity of the fibroblast growthfactor-receptors (FGFR); c) compounds targeting, decreasing orinhibiting the activity of the insulin-like growth factor receptor I(IGF-IR), such as compounds which target, decrease or inhibit theactivity of IGF-IR, especially compounds which inhibit the kinaseactivity of IGF-I receptor, or antibodies that target the extracellulardomain of IGF-I receptor or its growth factors; d) compounds targeting,decreasing or inhibiting the activity of the Trk receptor tyrosinekinase family, or ephrin B4 inhibitors; e) compounds targeting,decreasing or inhibiting the activity of the AxI receptor tyrosinekinase family; f) compounds targeting, decreasing or inhibiting theactivity of the Ret receptor tyrosine kinase; g) compounds targeting,decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosinekinase, such as imatinib; h) compounds targeting, decreasing orinhibiting the activity of the C-kit receptor tyrosine kinases, whichare part of the PDGFR family, such as compounds which target, decreaseor inhibit the activity of the c-Kit receptor tyrosine kinase family,especially compounds which inhibit the c-Kit receptor, such as imatinib;i) compounds targeting, decreasing or inhibiting the activity of membersof the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase)and mutants, such as compounds which target decrease or inhibit theactivity of c-Abl family members and their gene fusion products, such asan N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib(AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; ordasatinib (BMS-354825); j) compounds targeting, decreasing or inhibitingthe activity of members of the protein kinase C (PKC) and Raf family ofserine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK,PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/ormembers of the cyclin-dependent kinase family (CDK) includingstaurosporine derivatives, such as midostaurin; examples of furthercompounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1,Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521;LY333531/LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (aP13K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting,decreasing or inhibiting the activity of protein-tyrosine kinaseinhibitors, such as compounds which target, decrease or inhibit theactivity of protein-tyrosine kinase inhibitors include imatinib mesylate(Gleevec™) or tyrphostin such as Tyrphostin A23/RG-50810; AG 99;Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; TyrphostinB44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494;Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin); l) compounds targeting, decreasing orinhibiting the activity of the epidermal growth factor family ofreceptor tyrosine kinases (EGFR₁ ErbB2, ErbB3, ErbB4 as homo- orheterodimers) and their mutants, such as compounds which target,decrease or inhibit the activity of the epidermal growth factor receptorfamily are especially compounds, proteins or antibodies which inhibitmembers of the EGF receptor tyrosine kinase family, such as EGFreceptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands,CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab(Erbitux™), Iressa, Tarceva, OSI-774, CI-1033, EKB-569, GW-2016, E1.1,E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting,decreasing or inhibiting the activity of the c-Met receptor, such ascompounds which target, decrease or inhibit the activity of c-Met,especially compounds which inhibit the kinase activity of c-Metreceptor, or antibodies that target the extracellular domain of c-Met orbind to HGF, n) compounds targeting, decreasing or inhibiting the kinaseactivity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/orpan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib,pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, andruxolitinib; o) compounds targeting, decreasing or inhibiting the kinaseactivity of PI3 kinase (PI3K) including but not limited to ATU-027,SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib,pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, andidelalisib; and; and q) compounds targeting, decreasing or inhibitingthe signaling effects of hedgehog protein (Hh) or smoothened receptor(SMO) pathways, including but not limited to cyclopamine, vismodegib,itraconazole, erismodegib, and IPI-926 (saridegib).

The term “PI3K inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against one or more enzymes in thephosphatidylinositol-3-kinase family, including, but not limited toPI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α,p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87.Examples of PI3K inhibitors useful in this invention include but are notlimited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474,buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147,XL-765, and idelalisib.

The term “BTK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against Bruton's Tyrosine Kinase(BTK), including, but not limited to AVL-292 and ibrutinib.

The term “SYK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against spleen tyrosine kinase(SYK), including but not limited to PRT-062070, R-343, R-333, Excellair,PRT-062607, and fostamatinib

Further examples of BTK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2008039218 and WO2011090760, the entirety of which areincorporated herein by reference.

Further examples of SYK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2003063794, WO2005007623, and WO2006078846, the entirety ofwhich are incorporated herein by reference.

Further examples of PI3K inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2004019973, WO2004089925, WO2007016176, U.S. Pat. No.8,138,347, WO2002088112, WO2007084786, WO2007129161, WO2006122806,WO2005113554, and WO2007044729 the entirety of which are incorporatedherein by reference.

Further examples of JAK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2009114512, WO2008109943, WO2007053452, WO2000142246, andWO2007070514, the entirety of which are incorporated herein byreference.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g. unrelated to protein or lipid kinaseinhibition e.g. thalidomide (Thalomid™) and TNP-470.

Examples of proteasome inhibitors useful for use in combination withcompounds of the invention include, but are not limited to bortezomib,disulfuram, epigallocatechin-3-gallate (EGCG), salinosporamide A,carfilzomib, ONX-0912, CEP-18770, and MLN9708.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,or CDC25, such as okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes include, but arenot limited to, retinoic acid, α- γ- or δ-tocopherol or α- γ- orδ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is notlimited to, Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, such as5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. Etridonic acid is marketedunder the trade name Didronel™. Clodronic acid is marketed under thetrade name Bonefos™. Tiludronic acid is marketed under the trade nameSkelid™. Pamidronic acid is marketed under the trade name Aredia™.Alendronic acid is marketed under the trade name Fosamax™. Ibandronicacid is marketed under the trade name Bondranat™. Risedronic acid ismarketed under the trade name Actonel™. Zoledronic acid is marketedunder the trade name Zometa™. The term “mTOR inhibitors” relates tocompounds which inhibit the mammalian target of rapamycin (mTOR) andwhich possess antiproliferative activity such as sirolimus (Rapamune®),everolimus (Certican™), CCI-779 and ABT578.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulfate degradation. The termincludes, but is not limited to, PI-88. The term “biological responsemodifier” as used herein refers to a lymphokine or interferons.

The term “inhibitor of Ras oncogenic isoforms”, such as H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras; for example, a “farnesyltransferase inhibitor” such as L-744832, DK8G557 or R115777(Zarnestra™). The term “telomerase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of telomerase.Compounds which target, decrease or inhibit the activity of telomeraseare especially compounds which inhibit the telomerase receptor, such astelomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase include, but are not limited to, bengamideor a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasomeinclude, but are not limited to, Bortezomib (Velcade™) and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) asused herein includes, but is not limited to, collagen peptidomimetic andnonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamatepeptidomimetic inhibitor batimastat and its orally bioavailable analoguemarimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551)BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

The term “compounds used in the treatment of hematologic malignancies”as used herein includes, but is not limited to, FMS-like tyrosine kinaseinhibitors, which are compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors,which are compounds which target, decrease or inhibit anaplasticlymphoma kinase.

Compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R) are especially compounds, proteins orantibodies which inhibit members of the Flt-3R receptor kinase family,such as PKC412, midostaurin, a staurosporine derivative, SU11248 andMLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; othergeldanamycin related compounds; radicicol and HDAC inhibitors.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux,bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and2C4 Antibody. By antibodies is meant intact monoclonal antibodies,polyclonal antibodies, multispecific antibodies formed from at least 2intact antibodies, and antibodies fragments so long as they exhibit thedesired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of thecurrent invention can be used in combination with standard leukemiatherapies, especially in combination with therapies used for thetreatment of AML. In particular, compounds of the current invention canbe administered in combination with, for example, farnesyl transferaseinhibitors and/or other drugs useful for the treatment of AML, such asDaunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone,Idarubicin, Carboplatinum and PKC412.

Other anti-leukemic compounds include, for example, Ara-C, a pyrimidineanalog, which is the 2′-alpha-hydroxy ribose (arabinoside) derivative ofdeoxycytidine. Also included is the purine analog of hypoxanthine,6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds whichtarget, decrease or inhibit activity of histone deacetylase (HDAC)inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid(SAHA) inhibit the activity of the enzymes known as histonedeacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228(formerly FR901228), Trichostatin A and compounds disclosed in U.S. Pat.No. 6,552,065 including, but not limited to,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof andN-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, especially the lactatesalt. Somatostatin receptor antagonists as used herein refer tocompounds which target, treat or inhibit the somatostatin receptor suchas octreotide, and SOM230. Tumor cell damaging approaches refer toapproaches such as ionizing radiation. The term “ionizing radiation”referred to above and hereinafter means ionizing radiation that occursas either electromagnetic rays (such as X-rays and gamma rays) orparticles (such as alpha and beta particles). Ionizing radiation isprovided in, but not limited to, radiation therapy and is known in theart. See Hellman, Principles of Radiation Therapy, Cancer, in Principlesand Practice of Oncology, Devita et al., Eds., 4^(th) Edition, Vol. 1,pp. 248-275 (1993).

Also included are EDG binders and ribonucleotide reductase inhibitors.The term “EDG binders” as used herein refers to a class ofimmunosuppressants that modulates lymphocyte recirculation, such asFTY720. The term “ribonucleotide reductase inhibitors” refers topyrimidine or purine nucleoside analogs including, but not limited to,fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine,5-fluorouracil, cladribine, 6-mercaptopurine (especially in combinationwith ara-C against ALL) and/or pentostatin. Ribonucleotide reductaseinhibitors are especially hydroxyurea or2-hydroxy-1H-isoindole-1,3-dione derivatives.

Also included are in particular those compounds, proteins or monoclonalantibodies of VEGF such as1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof,1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate;Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474;SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGFreceptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such asMacugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody,Angiozyme (RPI 4610) and Bevacizumab (Avastin™)

Photodynamic therapy as used herein refers to therapy which uses certainchemicals known as photosensitizing compounds to treat or preventcancers. Examples of photodynamic therapy include treatment withcompounds, such as Visudyne™ and porfimer sodium.

Angiostatic steroids as used herein refers to compounds which block orinhibit angiogenesis, such as, e.g., anecortave, triamcinolone,hydrocortisone, 11-α-epihydrocotisol, cortexolone,17α-hydroxyprogesterone, corticosterone, desoxycorticosterone,testosterone, estrone and dexamethasone.

Implants containing corticosteroids refers to compounds, such asfluocinolone and dexamethasone.

Other chemotherapeutic compounds include, but are not limited to, plantalkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

The compounds of the invention are also useful as co-therapeuticcompounds for use in combination with other drug substances such asanti-inflammatory, bronchodilatory or antihistamine drug substances,particularly in the treatment of obstructive or inflammatory airwaysdiseases such as those mentioned hereinbefore, for example aspotentiators of therapeutic activity of such drugs or as a means ofreducing required dosaging or potential side effects of such drugs. Acompound of the invention may be mixed with the other drug substance ina fixed pharmaceutical composition or it may be administered separately,before, simultaneously with or after the other drug substance.Accordingly the invention includes a combination of a compound of theinvention as hereinbefore described with an anti-inflammatory,bronchodilatory, antihistamine or anti-tussive drug substance, saidcompound of the invention and said drug substance being in the same ordifferent pharmaceutical composition.

Suitable anti-inflammatory drugs include steroids, in particularglucocorticosteroids such as budesonide, beclomethasone dipropionate,fluticasone propionate, ciclesonide or mometasone furoate; non-steroidalglucocorticoid receptor agonists; LTB4 antagonists such LY293111,CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4antagonists such as montelukast and zafirlukast; PDE4 inhibitors suchcilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A(Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline(Almirall Prodesfarma), PD189659/PD168787 (Parke-Davis), AWD-12-281(Asta Medica), CDC-801 (Celgene), SeICID™ CC-10004 (Celgene),VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2aagonists; A2b antagonists; and beta-2 adrenoceptor agonists such asalbuterol (salbutamol), metaproterenol, terbutaline, salmeterolfenoterol, procaterol, and especially, formoterol and pharmaceuticallyacceptable salts thereof. Suitable bronchodilatory drugs includeanticholinergic or antimuscarinic compounds, in particular ipratropiumbromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), andglycopyrrolate.

Suitable antihistamine drug substances include cetirizine hydrochloride,acetaminophen, clemastine fumarate, promethazine, loratidine,desloratadine, diphenhydramine and fexofenadine hydrochloride,acrivastine, astemizole, azelastine, ebastine, epinastine, mizolastineand terfenadine.

Other useful combinations of compounds of the invention withanti-inflammatory drugs are those with antagonists of chemokinereceptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8,CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 andSCH-D, and Takeda antagonists such asN-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminiumchloride (TAK-770).

The structure of the active compounds identified by code numbers,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

A compound of the current invention may also be used in combination withknown therapeutic processes, for example, the administration of hormonesor radiation. In certain embodiments, a provided compound is used as aradiosensitizer, especially for the treatment of tumors which exhibitpoor sensitivity to radiotherapy.

A compound of the current invention can be administered alone or incombination with one or more other therapeutic compounds, possiblecombination therapy taking the form of fixed combinations or theadministration of a compound of the invention and one or more othertherapeutic compounds being staggered or given independently of oneanother, or the combined administration of fixed combinations and one ormore other therapeutic compounds. A compound of the current inventioncan besides or in addition be administered especially for tumor therapyin combination with chemotherapy, radiotherapy, immunotherapy,phototherapy, surgical intervention, or a combination of these.Long-term therapy is equally possible as is adjuvant therapy in thecontext of other treatment strategies, as described above. Otherpossible treatments are therapy to maintain the patient's status aftertumor regression, or even chemopreventive therapy, for example inpatients at risk.

Those additional agents may be administered separately from an inventivecompound-containing composition, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a compound of thepresent invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, the present inventionprovides a single unit dosage form comprising a compound of the currentinvention, an additional therapeutic agent, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.

The amount of both an inventive compound and additional therapeuticagent (in those compositions which comprise an additional therapeuticagent as described above) that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Preferably,compositions of this invention should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of an inventive compound can beadministered.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and the compound of this invention mayact synergistically. Therefore, the amount of additional therapeuticagent in such compositions will be less than that required in amonotherapy utilizing only that therapeutic agent. In such compositionsa dosage of between 0.01-1,000 μg/kg body weight/day of the additionaltherapeutic agent can be administered.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention, or pharmaceutical compositions thereof,may also be incorporated into compositions for coating an implantablemedical device, such as prostheses, artificial valves, vascular grafts,stents and catheters. Vascular stents, for example, have been used toovercome restenosis (re-narrowing of the vessel wall after injury).However, patients using stents or other implantable devices risk clotformation or platelet activation. These unwanted effects may beprevented or mitigated by pre-coating the device with a pharmaceuticallyacceptable composition comprising a kinase inhibitor. Implantabledevices coated with a compound of this invention are another embodimentof the present invention.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

Example 1 Synthesis of Intermediate 5 (Ethyl2-[3-hydroxy-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]acetate)

Step 1. Synthesis of 1,3-diethyl 2-(3-oxocyclohexyl)propanedioate

Into a 1 L round-bottom flask placed a solution of cyclohex-2-en-1-one(15.00 g, 156.04 mmol, 1.00 equiv) in anhydrous THF (300 mL) was added1,3-diethyl 2-bromopropanedioate (56.00 g, 234.25 mmol, 1.50 equiv), Inpowder (18.00 g, 1.00 equiv) and TMSCl (87.00 g, 800.81 mmol, 5.00equiv) under nitrogen. The resulting solution was stirred for 30 min atroom temperature and quenched by the addition of 200 mL of saturatedaqueous sodium carbonate, extracted with 3×300 mL of ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated under vacuum. The residue was purifiedby silica gel column chromatography with ethyl acetate/petroleum ether(1:5) to give 1,3-diethyl 2-(3-oxocyclohexyl)propanedioate (28.50 g,71%) as yellow oil.

Step 2. Synthesis of ethyl 2-(3-oxocyclohexyl)acetate

A solution of 1,3-diethyl 2-(3-oxocyclohexyl)propanedioate (28.50 g,111.20 mmol, 1.00 equiv) and sodium chloride (7.02 g, 1.10 equiv) in amixture of water (4 mL)/DMSO (80 mL) was heated for 24 h at 180° C. inan oil bath. After cooled down to r.t, the reaction was then dilutedwith water, extracted with 3×300 mL of ethyl acetate. The organic layerswere combined, washed with water and brine, dried over anhydrous sodiumsulfate and concentrated under vacuum to give ethyl2-(3-oxocyclohexyl)acetate (22.7 g, crude) as yellow oil which was usedfor next step without purification.

Step 3. Synthesis of ethyl2-amino-5-(2-ethoxy-2-oxoethyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate

Into a 500-mL round-bottom flask contained a solution of ethyl2-(3-oxocyclohexyl)acetate (22.70 g, crude), ethyl 2-cyanoacetate (16.30g, 144.10 mmol, 1.20 equiv), S (4.70 g, 1.20 equiv) and Et₂NH (10.50 g,1.20 equiv) in 200 mL of ethanol was stirred overnight at roomtemperature. The solvent was removed under reduced pressure. The residuewas purified by silica gel column chromatography with ethylacetate/petroleum ether (1:5) to afford ethyl2-amino-5-(2-ethoxy-2-oxoethyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate(20.68 g) as yellow oil. LC-MS (ES, m/z): 312 [M+H]⁺.

Step 4. Synthesis of ethyl2-[3-hydroxy-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]acetate

A solution of ethyl2-amino-5-(2-ethoxy-2-oxoethyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate(20.68 g, 66.41 mmol, 1.00 equiv) in 100 mL of formamide was stirredovernight at 180° C. in an oil bath. After the starting materialdisappeared, the reaction was cooled to room temperature and quenchedwith water, extracted with 3×200 mL of ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was purified bysilica gel column chromatography with ethyl acetate/petroleum ether(1:2) to afford ethyl2-[3-hydroxy-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]acetate(10.10 g, 52%) as yellow oil. LC-MS (ES, m/z): 293 [M+H]⁺.

Example 2 Synthesis of Ethyl2-(4-(((1r,4r)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidin-6-yl)acetate(I-21)

Step 1. Synthesis of ethyl2-[3-hydroxy-8-thia-4,6-diazatricyclo[7.4.0.0̂[2,7]]trideca-1(9),2(7),3,5,10,12-hexaen-12-yl]acetate

A mixture of ethyl2-[3-hydroxy-8-thia-4,6-diazatricyclo[7.4.0.0̂[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]acetate(3.00 g, 10.26 mmol, 1.00 equiv) and DDQ (5.83 g, 25.68 mmol, 2.50equiv) in 1,4-dioxane (30 mL) was stirred for 2 h at 90° C. in an oilbath under nitrogen. The reaction mixture was cooled to room temperatureand quenched with saturated aqueous Na₂CO₃, extracted with 3×40 mL ofethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate and concentrated under vacuum. The residuewas purified by silica gel column chromatography with ethylacetate/petroleum ether (1:1) to provide the desired ethyl2-[3-hydroxy-8-thia-4,6-diazatricyclo[7.4.0.0̂[2,7]]trideca-1(9),2(7),3,5,10,12-hexaen-12-yl]acetate(2.00 g, 68%) as a yellow solid. LCMS (ES, m/z): 289 (M+H⁺).

Step 2. Synthesis of ethyl2-[3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0̂[2,7]]trideca-1(9),2(7),3,5,10,12-hexaen-12-yl]acetate

A solution of ethyl2-[3-hydroxy-8-thia-4,6-diazatricyclo[7.4.0.0̂[2,7]]trideca-1(9),2(7),3,5,10,12-hexaen-12-yl]acetate(2.10 g, 7.28 mmol, 1.00 equiv) in POCl₃ (23 mL) was stirred for 1 h at90° C. in an oil bath. The reaction mixture was cooled to roomtemperature and concentrated under reduced pressure. The residuedissolved in EtOAc was poured into a cooled saturated aqueous sodiumbicarbonate, extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over sodium sulfate and concentrated invacuo. The residue was purified by a silica gel column chromatographywith ethyl acetate/petroleum ether (1:5) to afford ethyl2-[3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0̂[2,7]]trideca-1(9),2(7),3,5,10,12-hexaen-12-yl]acetate(1.61 g, 72%) as a white solid. LCMS (ES, m/z): 307 and 309 (M+H⁺).

Step 3. Synthesis of ethyl2-(4-(((trans)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidin-6-yl)acetate

A solution of ethyl2-[3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(13),2(7),3,5,9,11-hexaen-12-yl]acetate(500 mg, 1.63 mmol, 1.00 equiv) in MeCN (100 mL) was added potassiumcarbonate (2.2 g, 15.92 mmol, 10.00 equiv), TEA (495 mg, 4.89 mmol, 3.00equiv) and trans-4-(morpholin-4-yl)cyclohexan-1-amine (1.5 g, 8.14 mmol,5.00 equiv) subsequently at room temperature under nitrogen. Theresulting solution was stirred overnight at 80° C. and cooled down tor.t. The reaction was quenched with water, extracted with 3×100 mL ofethyl acetate. The organic layers were combined, dried over anhydroussodium sulfate and concentrated under vacuum. The residue was purifiedby silica gel column chromatography with dichloromethane/methanol (20/1)to give 300 mg (40%) of the corresponding ethyl2-(4-(((trans)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidin-6-yl)acetateas an off-white solid. LCMS: (ES, m/z) 455 (M+H⁺). ¹H-NMR (300 MHz,CDCl₃) δ 8.57 (s, 1H), 7.88-7.85 (d, 1H), 7.71 (s, 1H), 7.42-7.40 (d,1H), 5.33-5.31 (d, 1H), 4.30-4.21 (m, 1H), 4.19-4.09 (q, 2H), 3.81 (s,2H), 3.75 (s, 4H), 2.61 (s, 4H), 2.38 (s, 3H), 2.05 (s, 2H), 1.55-1.52(d, 2H), 1.45-1.41 (m, 2H), 1.31-1.27 (t, 3H).

Example 3 Synthesis of(1r,4r)-N1-(benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-N4,N4-dimethylcyclohexane-1,4-diamine(I-2)

Step 1: Synthesis of ethyl2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate

A solution of cyclohexanone (9.8 g, 99.85 mmol, 1.00 equiv) in ethanol(50 mL) was added ethyl 2-cyanoacetate (11.3 g, 99.90 mmol, 1.00 equiv),diethylamine (7.3 g, 99.81 mmol, 1.00 equiv) and S (3.2 g, 0.10 mol,1.00 equiv) was stirred for 24 h at room temperature. The solids formedwere collected by filtration and then washed with EtOAc (20 mL). Thesolid was dried in an oven at 45° C. for 2 h to give 18 g (80%) of thedesired ethyl 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylateas a yellow solid.

Step 2: Synthesis of8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-ol

Into a 100-mL round-bottom flask containing a solution of ethyl2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (4.06 g, 18.02mmol, 1.00 equiv) in 100 mL of formamide was stirred for 8 h at 160° C.in an oil bath under nitrogen. The reaction mixture was cooled to 0° C.and diluted with water. The solids were filtered and precipitated withethyl acetate to provide8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-ol(3.0 g, 81%) as a light yellow solid.

Step 3: Synthesis of8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5,10,12-hexaen-3-ol

A solution of8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-ol(2.06 g, 9.99 mmol, 1.00 equiv) in 1,4-dioxane (30 mL) was added DDQ(5.68 g, 25.02 mmol, 2.50 equiv) ar room temperature under nitrogen andthe resulting solution was stirred overnight at 90° C. in an oil bath.After cooling to room temperature, the reaction was quenched withsaturated aqueous sodium bicarbonate, and extracted with 3×100 mL ofdichloromethane. The organic layers were combined, washed with brine,dried over anhydrous sodium sulfate, and concentrated under vacuum toprovide 1.8 g (crude) of8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5,10,12-hexaen-3-olas a yellow solid.

Step 4: Synthesis of3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2,4,6,10,12-hexaene

Into a 100-mL round-bottom flask, was placed a solution of8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2,4,6,10,12-hexaen-3-ol(2.0 g, 9.89 mmol, 1.00 equiv) in 1,4-dioxane (15 mL) and POCl₃ (4.5 g,29.35 mmol, 2.97 equiv) under nitrogen. The resulting solution wasstirred for 4 h at 90° C. The excess amount of POCl₃ was removed underreduced pressure and the residue was diluted with DCM. The resultingmixture was poured into a cooled saturated aqueous sodium bicarbonate,extracted with DCM, dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was purified by silica gel columnchromatography with ethyl acetate/petroleum ether (1:10) to afford3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2,4,6,10,12-hexaene(0.9 g, 41%) as a white solid.

Step 5: Synthesis of(1r,4r)-N1-(benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-N4,N4-dimethylcyclohexane-1,4-diamine

A solution of3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5,10,12-hexaene(1.25 g, 5.66 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL) wasadded trans-dimethylcyclohexane-1,4-diamine dihydrochloride (1.66 g,7.72 mmol, 1.36 equiv) and triethylamine (1.14 g, 11.27 mmol, 1.99equiv) at room temperature under nitrogen. The resulting solution wasstirred overnight at 50° C. in an oil bath. The resulting mixture waspartially evaporated under reduced pressure. The solids were collectedby filtration, washed with 10 mL of DCM and 5 mL of water. After driedin an oven at 45° C. for 2 h, the desired compound(1r,4r)-N1-(benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-N4,N4-dimethylcyclohexane-1,4-diaminewas obtained (1.0403 g, 51%) as an off-white solid. LC-MS: (ES, m/z) 327[M−0.95HCl+H]⁺. ¹H-NMR: (300 MHz, DMSO) δ 1.50-1.80 (4H, m), 2.00-2.20(4H, m), 2.74 (6H, s), 3.09-3.25 (1H, m), 4.25-4.45 (1H, m), 7.03 (1H,d, J=8.1 Hz), 7.52-7.63 (2H, m), 8.09 (1H, d, J=7.2 Hz), 8.44 (1H, d,J=7.2 Hz), 8.51 (1H, s), 10.45 (1H, brs).

Example 4 Synthesis of4-((1r,4r)-4-(benzo[4,5]thieno[2,3-d]pyrimidin-4-yloxy)cyclohexyl)morpholine(I-16)

Sodium hydride (70 mg, 1.75 mmol, 3.00 equiv, 60% dispersion in mineraloil) was treated with trans-4-(morpholin-4-yl)cyclohexan-1-ol (214 mg,1.16 mmol, 2.00 equiv) in 20 mL of distilled THF at room temperature for30 minutes. Then 4-chlorobenzo[4,5]thieno[2,3-d]pyrimidine (128 mg, 0.58mmol, 1.00 equiv) was added to the mixture and the resulting solutionwas stirred for 5 h at room temperature. The reaction was then quenchedby the addition of 5 mL of H₂O, extracted with 3×30 mL ofdichloromethane. The organic layers were combined, washed with brine,dried over sodium sulfate and concentrated under vacuum. The crudeproduct (100 mg) was purified by Prep-HPLC with the following conditions(Waters): Column, Xbridge Prep C18, 5 um, 19*50 mm; mobile phase, waterwith 0.05% NH₄HCO₃ and CH₃CN (10% CH₃CN up to 35% in 10 min, up to 95%in 1.5 min, down to 10% in 1.5 min); Flow rate: 20 mL/min; UV detectionat 254/220 nm. This resulted in 29 mg of4-((1r,4r)-4-(benzo[4,5]thieno[2,3-d]pyrimidin-4-yloxy)cyclohexyl)morpholineas a white solid. LC-MS: (ES, m/z) 370 (M+H⁺). ¹H-NMR (300 MHz, CD₃OD) δ1.45-1.60 (2H, m), 1.66-1.80 (2H, m), 2.10 (2H, m), 2.41 (2H, m), 2.68(4H, m), 3.78 (4H, m), 5.40 (1H, m), 7.52-7.56 (2H, m), 7.96 (1H, m),8.40 (1H, m), 8.65 (1H, s).

Example 5 Synthesis of(1r,4r)-4-(benzo[4,5]thieno[2,3-d]pyrimidin-4-yloxy)-N,N-dimethylcyclohexanamine(I-12)

Sodium hydride (82 mg, 2.05 mmol, 3.01 equiv, 60% dispersion in mineraloil) was treated with trans-4-(dimethylamino)cyclohexan-1-ol (195 mg,1.36 mmol, 2.00 equiv) in 15 mL of distilled THF at room temperature for1 h under nitrogen. Then a solution of4-chlorobenzo[4,5]thieno[2,3-d]pyrimidine (150 mg, 0.68 mmol, 1.00equiv) in 5 mL of THF was added via syringe and the resulting solutionwas stirred overnight at room temperature. The reaction was quenchedwith water, extracted with DCM (5×30 mL), washed with brine, dried oversodium sulfate and concentrated under vacuum. The residue was purifiedby silica gel column chromatography with dichloromethane/methanol(10:1-5:1) to give the desired(1r,4r)-4-(benzo[4,5]thieno[2,3-d]pyrimidin-4-yloxy)-N,N-dimethylcyclohexanamine(22.1 mg) as a white solid. LCMS (ES, m/z) 328 (M+H⁺); ¹H-NMR (400 MHz,CDCl₃) δ 1.50-1.61 (2H, m), 1.69-1.79 (2H, m), 2.05-2.09 (2H, m), 2.36(6H, s), 2.38-2.44 (2H, m), 5.42 (1H, m), 7.51-7.57 (2H, m), 7.89-7.92(1H, m), 8.41-8.45 (1H, m), 8.72 (1H, s).

Example 6 Synthesis of(1r,4r)-N1-(benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)cyclohexane-1,4-diaminehydrochloride (I-11) Step 1: Synthesis of tert-butyl((1r,4r)-4-(benzo[4,5]thieno[2,3-d]pyrimidin-4-ylamino)cyclohexyl)carbamate

A solution of 4-chlorobenzo[4,5]thieno[2,3-d]pyrimidine (220 mg, 1.00mmol, 1.00 equiv) in 10 mL of DMF was added tert-butyltrans-N-(4-aminocyclohexyl)carbamate (320 mg, 1.49 mmol, 1.50 equiv) andtriethylamine (200 mg, 1.98 mmol, 2.00 equiv) and the resulting solutionwas stirred overnight at room temperature. The reaction was thenquenched with water, extracted with 3×50 mL of ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated under vacuum. The residue was purifiedby silica gel column chromatography with ethyl acetate/petroleum ether(1:4) to afford tert-butyl((1r,4r)-4-(benzo[4,5]thieno[2,3-d]pyrimidin-4-ylamino)cyclohexyl)carbamate(0.25 g, 63%) as a white solid. LCMS (ES, m/z): 399 (M+H⁺).

Step 2. Synthesis of(1r,4r)-N1-(benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)cyclohexane-1,4-diaminehydrochloride (I-11)

A solution of tert-butyl((1r,4r)-4-(benzo[4,5]thieno[2,3-d]pyrimidin-4-ylamino)cyclohexyl)carbamate(500 mg, 1.25 mmol, 1.00 equiv) in dichloromethane (10 mL) was addedhydrochloric acid (12 M, 1 mL) at 0° C. The resulting solution wasstirred for 2 h at room temperature and concentrated in vacuo. Thesolution was adjusted to pH 9 with sodium bicarbonate (1 mol/L) and thesolids were collected by filtration, and washed with 5 mL of water.After drying in an oven at 45° C. for 2 h, the desired(1r,4r)-N1-(benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)cyclohexane-1,4-diaminehydrochloride (362.4 mg, 86%) was obtained as a white solid. LC-MS: (ES,m/z) 299 (M+H⁺). ¹H-NMR: (400 MHz, CD₃OD) δ 8.48 (s, 1H), 8.27 (d, 1H),8.00 (d, 1H), 7.63-7.53 (m, 2H), 7.45-7.37 (m, 1H), 3.24-3.15 (m, 1H),2.30 (d, 2H), 2.18 (d, 2H), 1.79-1.66 (m, 4H).

Example 7 Ethyl4-(((1r,4r)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylate(I-8)

Synthesis of 3-hydroxycyclohexane-1-carboxylic acid

A 1 L pressure tank reactor (60 atm) containing a solution of3-hydroxybenzoic acid (30 g, 217.20 mmol, 1.00 equiv), Raney Ni (5 g)and sodium hydroxide (6.4 g, 160.00 mmol, 0.74 equiv) in water (500 mL)was introduced H₂ (gas, 60 atm) and the resulting solution was stirredovernight at 150° C. After completion of the reaction, the reactiontemperature was cooled down to room temperature and the solids werefiltered out by filtration. The resulting solution was neutralized with12 M HCl, extracted with 6×100 mL of tetrahydrofuran. The combinedorganic layers were dried over sodium sulfate and concentrated undervacuum to provide 3-hydroxycyclohexane-1-carboxylic acid (11 g, crude)as a white solid.

Synthesis of 3-oxocyclohexane-1-carboxylic acid

The Jones oxidation reagent was prepared from sulfuric acid (30 mL),CrO₃ (8.1 g) and H₂O (30 mL) in an ice/water bath. A solution of3-hydroxycyclohexane-1-carboxylic acid (11 g, 76.3 mmol, 1.00 equiv) inacetone (150 mL) was added slowly the prepared Jones reagent at 0° C. in30 min. After addition, the resulting solution was stirred for 2 h atroom temperature and the solids were filtered out. The resultingsolution was extracted with DCM (3×100 mL). The combined organic layerswere washed with brine and dried over sodium sulfate and concentratedunder vacuum to give the desired 3-oxocyclohexane-1-carboxylic acid (8.7g, crude) as a yellow oil.

Synthesis of ethyl 3-oxocyclohexane-1-carboxylate

A solution of 3-oxocyclohexane-1-carboxylic acid (8.7 g, 61.20 mmol,1.00 equiv) and ethanol (21 mL) in toluene (150 mL) was addedp-toluenesulfonic acid (250 mg) at room temperature and the resultingsolution was heated to reflux overnight in presence of a Dean-Stark.After completion, the resulting mixture was concentrated under vacuumand the residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:4) to give the desired ethyl3-oxocyclohexane-1-carboxylate (7.5 g, 72%) as white oil.

Synthesis of ethyl3-(1-cyano-2-ethoxy-2-oxoethylidene)cyclohexane-1-carboxylate

Into a 500-mL round-bottom flask, was placed ethyl3-oxocyclohexane-1-carboxylate (7 g, 41.13 mmol, 1.00 equiv), ethyl2-cyanoacetate (6.5 g, 57.46 mmol, 1.40 equiv), AcOH (0.8 mL) and NH₄OAc(300 mg) in toluene (150 mL). The resulting solution was heated toreflux overnight in presence of a Dean-Stark. After the starting 4 wasconsumed completely, the resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:9) to give the corresponding ethyl3-(1-cyano-2-ethoxy-2-oxoethylidene)cyclohexane-1-carboxylate (8.0 g,73%) as yellow oil.

Step 5. Synthesis of 3,5-diethyl2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3,5-dicarboxylate

A solution of ethyl3-(1-cyano-2-ethoxy-2-oxoethylidene)cyclohexane-1-carboxylate (8 g,30.15 mmol, 1.00 equiv) in methanol (100 mL) was added S (970 mg, 30.31mmol, 1.01 equiv) and Et₂NH (3.2 mL) and the resulting solution wasstirred for 2 h at 50° C. under nitrogen. The resulting mixture wasconcentrated under vacuum and the residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:9) to give the resulted3,5-diethyl2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3,5-dicarboxylate (8.0 g,88%) as a yellow solid.

Synthesis of ethyl4-hydroxy-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylate

A solution of 3,5-diethyl2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3,5-dicarboxylate (8 g,26.90 mmol, 1.00 equiv) in formamide (150 mL) was added formamidineacetate (10 g, 96.05 mmol, 3.57 equiv) at room temperature undernitrogen. The resulting solution was stirred for 4 h at 180° C. Aftercooling, the resulting solution was diluted with 200 mL of EtOAc, washedwith water and brine, dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:4) give the desired ethyl4-hydroxy-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylate(4.1 g, 55%) as a yellow solid.

Step 7. Synthesis of ethyl4-hydroxybenzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylate

To a 250-mL round-bottom flask was placed a solution of ethyl4-hydroxy-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylate(4.0 g, 14.39 mmol, 1.00 equiv) in 1.4-dioxane (50 mL) was added DDQ (8g, 35.24 mmol, 2.45 equiv) at room temperature. The resulting solutionwas stirred for 3 h at 90° C. under nitrogen. After cooling, thereaction was quenched with saturated aqueous Na₂CO₃. The solids werefiltered out and the filtration was extracted with 3×100 mL ofdichloromethane. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:1) to give the resulted ethyl3-hydroxy-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5,10,12-hexaene-12-carboxylate(2.2 g, 56%) as a brown solid.

Step 8. Synthesis of ethyl4-chlorobenzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylate

Into a 100-mL round-bottom flask containing a solution of ethyl4-hydroxybenzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylate (2.2 g, 4.01mmol, 1.00 equiv) in 1.4-dioxane (60 mL) was added POCl₃ (30 mL) at roomtemperature under nitrogen. The resulting solution was stirred for 2 hat 90° C. and concentrated under vacuum. The residue dissolved in DCMand poured into a cooled saturated aqueous Na₂CO₃, extracted with 3×100mL of dichloromethane. The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:9) to give 1.8 g (77%) of thecorresponding ethyl4-chlorobenzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylate as a yellowsolid.

Step 9. Synthesis of ethyl4-(((1r,4r)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylate

A solution of ethyl4-chlorobenzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylate (500 mg, 1.7mmol, 1.00 equiv), 4-(morpholin-4-yl)cyclohexan-1-amine chloride (1.1 g,4.25 mmol, 2.5 equiv) and potassium carbonate (2.3 g, 17 mmol, 10.17equiv) in CH₃CN (100 mL) was Et₃N (2 mL) at room temperature undernitrogen. The resulting solution was heated to reflux overnight. Thesolids were filtered out and the filtrate was concentrated under vacuum.The residue was applied onto a silica gel column withdichloromethane/methanol (10:1) to give the desired ethyl3-[[4-(morpholin-4-yl)cyclohexyl]amino]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5,10,12-hexaene-12-carboxylate(500 mg, 66%) as a yellow solid. LCMS: (ES, m/z) 441 [M+H]⁺. ¹H-NMR (300MHz, CD₃OD): δ 1.44-1.53 (4H, m), 1.57-1.65 (3H, m), 2.24-2.29 (2H, m),2.25-2.33 (3H, m), 2.56-2.67 (4H, m), 3.45-3.75 (4H, m), 4.31-4.43 (1H,m), 4.45-4.50 (2H, m), 8.07-8.16 (2H, m), 8.49 (1H, s), 8.78 (1H, s).

Example 8 Synthesis of2-(4-(((1r,4r)-4-morpholinocyclohexyl)oxy)benzo[4,5]thieno[2,3-d]pyrimidin-6-yl)ethanol0367(I-13)

Step 1. Synthesis of2-(4-chlorobenzo[4,5]thieno[2,3-d]pyrimidin-6-yl)ethanol

Into a 100-mL round-bottom flask, was placed a solution of ethyl2-[3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5,10,12-hexaen-12-yl]acetate(850 mg, 2.77 mmol, 1.00 equiv) in freshly distilled THF (15 mL) cooleddown to −78° C. in a liquid N₂/ethanol bath under nitrogen. Then DIBAL-H(4.42 mL, 2.00 equiv) was added dropwise with stirring at −78° C. in 10min and the resulting solution was stirred for 2 h at this temperature.The resulting solution was allowed to react, with stirring, for anadditional 1 h at room temperature and quenched with water, extractedwith 3×100 mL of ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (4/1) to give the2-(4-chlorobenzo[4,5]thieno[2,3-d]pyrimidin-6-yl)ethanol (500 mg, 68%)as a yellow solid. LCMS (ES, m/z): 265 and 267 (M+H⁺).

Step 2. Synthesis of6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-chlorobenzo[4,5]thieno[2,3-d]pyrimidine

A solution of 2-(4-chlorobenzo[4,5]thieno[2,3-d]pyrimidin-6-yl)ethanol(500 mg, 1.89 mmol, 1.00 equiv), TBSCl (425 mg, 2.83 mmol, 1.50 equiv)and 1H-imidazole (232 mg, 3.41 mmol, 1.80 equiv) in distilledN,N-dimethylformamide (10 mL) was stirred overnight at room temperature.The resulting solution was diluted with water, extracted with 3×80 mL ofethyl acetate. The organic layers were combined, washed with brine,dried over sodium sulfate and concentrated under reduced pressure. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1/4) to afford 500 mg (70%) of the desired12-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0̂[2,7]]trideca-1(9),2(7),3,5,10,12-hexaneas a white solid. LCMS (ES, m/z): 379 and 381 (M+H⁺).

Step 3. Synthesis of4-((1r,4r)-4-((6-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)oxy)cyclohexyl)morpholine

Into a 50-mL 3-necked round-bottom flask containing a solution oftrans-4-(morpholin-4-yl)cyclohexan-1-ol (85 mg, 0.46 mmol, 1.93 equiv)in anhydrous tetrahydrofuran (4 mL) was added sodium hydride (60%dispersion in mineral oil, 80 mg, 2.00 mmol, 8.42 equiv) at 0° C. undernitrogen. After stirred for 1 h at room temperature, a solution of6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-chlorobenzo[4,5]thieno[2,3-d]pyrimidine(90 mg, 0.24 mmol, 1.00 equiv) in THF (3 mL) was added and the resultingsolution was stirred overnight at ambient temperature. The reaction wasthen quenched with water, extracted with 3×50 mL of ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1/1) toprovide 85 mg (68%) of the corresponding4-((1r,4r)-4-((6-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)oxy)cyclohexyl)morpholineas a white solid. LCMS (ES, m/z): 528 (M+H⁺).

Step 4. Synthesis of2-(4-(((1r,4r)-4-morpholinocyclohexyl)oxy)benzo[4,5]thieno[2,3-d]pyrimidin-6-yl)ethanol

A solution of4-((1r,4r)-4-((6-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)oxy)cyclohexyl)morpholine(700 mg, 1.33 mmol, 1.00 equiv) in 10 mL of THF was added TBAF (428 mg)and the resulting solution was stirred for 5 h at room temperature. Themixture was quenched with water, extracted with 3×100 mL of ethylacetate. The organic layers were combined, washed with brine, dried oversodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with dichloromethane/methanol/NH₄OH (10/1/0.05)to give the resulted2-(4-(((1r,4r)-4-morpholinocyclohexyl)oxy)benzo[4,5]thieno[2,3-d]pyrimidin-6-yl)ethanol(350 mg, 64%) as a off-white solid. LCMS: (ES, m/z) 414 (M+H⁺). ¹H-NMR(300 MHz, CDCl₃) δ 8.66 (s, 1H), 8.25 (s, 1H), 7.82-7.80 (d, 1H),7.26-7.18 (s, 1H), 5.41-5.38 (m, 1H), 3.98 (m, 2H), 3.76 (m, 4H),3.08-3.04 (t, 2H), 2.85 (m, 4H), 2.61 (m, 3H), 2.09-2.06 (d, 2H),1.77-1.53 (m, 5H).

Example 9 Synthesis of ethyl4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylate(I-5)

A solution of ethyl3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2,4,6,10,12-hexaene-12-carboxylate(500 mg, 1.71 mmol, 1.00 equiv) in butan-2-ol (15 mL) was addedtriethylamine (300 mg, 2.96 mmol, 1.74 equiv) andtrans-1-N,1-N-dimethylcyclohexane-1,4-diamine hydrochloride (730 mg,3.41 mmol, 2.00 equiv) and the resulting solution was stirred for 5 h at60° C. under nitrogen. After cooling, the resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with dichloromethane/methanol/NH₄OH (10:1:0.05) to provide 600 mg(88%) of the corresponding ethyl4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylateas a yellow solid. LC/MS (ES, m/z) 399 [M+H]⁺. ¹H-NMR (400 MHz, CDCl₃):δ 1.27-1.33 (1H, m), 1.33-1.66 (6H, m), 2.04-2.07 (2H, m), 2.34-2.50(9H, m), 4.28-4.31 (1H, m), 4.48-4.52 (2H, m), 5.45-5.47 (1H, d),7.97-7.99 (1H, d), 8.15-8.17 (1H, d), 8.52 (1H, s), 8.63 (1H, s).

Example 10 Synthesis ofN-((1r,4r)-4-morpholinocyclohexyl)benzo[4,5]thieno[2,3-d]pyrimidin-4-amine(I-4)

A solution of 4-chlorobenzo[4,5]thieno[2,3-d]pyrimidine (250 mg, 1.13mmol, 1.00 equiv) in anhydrous N,N-dimethylformamide (20 mL) wastrans-4-(morpholin-4-yl)cyclohexan-1-amine (415 mg, 2.25 mmol, 2.00equiv) and triethylamine (342 mg, 3.38 mmol, 3.00 equiv) at roomtemperature and the resulting solution was stirred overnight at 50° C.The resulting solution was diluted with 50 mL of brine, extracted with4×100 mL of dichloromethane. The organic layers were combined, waswashed with brine. The resulting mixture was dried and concentrated. Theresidue was applied onto a silica gel column withdichloromethane/MeOH/NH₄OH (30:1:0.05) to afford 256.6 mg (61%) of thecorrespondingN-((1r,4r)-4-morpholinocyclohexyl)benzo[4,5]thieno[2,3-d]pyrimidin-4-amineas a white solid. LC-MS: (ES, m/z) 369 (M+H⁺). ¹H NMR: (300 MHz, DMSO) δ1.41 (2H, m), 1.58-1.71 (2H, m), 1.82-1.93 (2H, m), 1.99-2.07 (2H, m),2.20-2.28 (1H, m), 2.49-2.51 (4H, m), 3.56-3.59 (4H, t, J=4.5 Hz),4.22-4.33 (1H, m), 6.90 (1H, d, J=7.8 Hz), 7.50-7.61 (2H, m), 8.06-8.10(1H, m), 8.34-8.48 (1H, d, J=13.5 Hz), 8.50 (1H, s).

Example 11 Synthesis of(1r,4r)-N1-(benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-N4-methylcyclohexane-1,4-diamine(I-9)

Step 1. Synthesis of tert-butyl((1r,4r)-4-(benzo[4,5]thieno[2,3-d]pyrimidin-4-ylamino)cyclohexyl)carbamate

A solution of 4-chlorobenzo[4,5]thieno[2,3-d]pyrimidine (1.50 g, 6.80mmol, 1.00 equiv) and tert-butyl trans-N-(4-aminocyclohexyl)carbamate(7.26 g, 33.88 mmol, 5.00 equiv) was added triethylamine (2.06 g, 20.36mmol, 3.00 equiv) in anhydrous DMF (20 mL) and stirred overnight at roomtemperature. The reaction was quenched with water, extracted with 3×80mL of ethyl acetate. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:2) to provided 2.46 g (91%) of the resultedtert-butyl((1r,4r)-4-(benzo[4,5]thieno[2,3-d]pyrimidin-4-ylamino)cyclohexyl)carbamateas a white solid. LC/MS (ES, m/z): 399 (M+H⁺).

Step 2. Synthesis of(1r,4r)-N1-(benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)cyclohexane-1,4-diamine

A solution of tert-butyl((1r,4r)-4-(benzo[4,5]thieno[2,3-d]pyrimidin-4-ylamino)cyclohexyl)carbamate(600 mg, 1.51 mmol, 1.00 equiv) in 60 mL of DCM was addedtrifluoroacetic acid (10 mL) at 0° C. and stirred for another 2 h atroom temperature. The resulting mixture was concentrated under vacuum togive 700 mg (100%) of the desired(1r,4r)-N1-(benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)cyclohexane-1,4-diamineas a yellow solid. LC/MS (ES, m/z): 299 (M+H⁺).

Step 3. Synthesis of compound(1r,4r)-N1-(benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-N4-methylcyclohexane-1,4-diamine

A solution of(trans)-N1-(benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)cyclohexane-1,4-diamine(618 mg, 2.07 mmol, 1.00 equiv), paraformaldehyde (450 mg) andtrifluoroacetic acid (15 mL) in DCE (50 mL) was stirred overnight at 65°C. The reaction mixture was cooled to room temperature and concentratedunder vacuum. The reaction was quenched with saturated aqueous sodiumcarbonate, extracted with 3×80 mL of dichloromethane. The organic phasewas concentrated under reduced pressure. The crude product (642 mg) waspurified by Prep-HPLC with the following conditions (Waters): Column,Xbridge Prep C18, 5 um, 19*50 m; mobile phase, water with 0.05% NH₄HCO₃and CH₃CN (12% CH₃CN up to 32% in 13 min, up to 95% in 2 min, down to12% in 2 min); Flow rate: 20 mL/min; UV detection at 254/220 nm. Theproduct-containing fractions were collected and partially evaporated toremove water and CH₃CN under reduced pressure. The residue waslyophilized overnight to give the desired product(1r,4r)-N1-(benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-N4-methylcyclohexane-1,4-diamine(200 mg) as a white solid. LC/MS (ES, m/z): 313 (M+H⁺). ¹H-NMR (300 MHz,CDCl₃) δ 8.59 (s, 1H), 7.93-7.91 (d, 1H), 7.91-7.80 (d, 1H), 7.56-7.46(m, 2H), 5.35-5.33 (d, 1H), 4.34-4.31 (m, 1H), 2.50 (s, 4H), 2.33 (s,2H), 2.12-2.09 (d, 2H), 1.49-1.31 (m, 4H).

Example 122-(4-(((1r,4r)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidin-6-yl)acetamide(I-18)

Into a saturated solution of ammonia (gas) in ethanol (50 mL) was addedethyl2-(3-[[4-(morpholin-4-yl)cyclohexyl]amino]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(13),2(7),3,5,9,11-hexaen-12-yl)acetate (100 mg, 0.22mmol, 1.00 equiv) and the resulting solution was sealed and stirredovernight at room temperature. After completion, the solvent was removedunder reduced pressure. The residue was applied onto a silica gel columnwith dichloromethane/methanol/NH₄OH (15:1:0.05) to provide the resulted2-(3-[[4-(morpholin-4-yl)cyclohexyl]amino]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(13),2(7),3,5,9,11-hexaen-12-yl)acetamide (38.5 mg, 41%)as a off-white solid. LC/MS: (ES, m/z) 426 [M+H]⁺. ¹H-NMR (400 MHz,CDCl₃) δ 8.60 (s, 1H), 7.93-7.91 (d, 1H), 7.75 (s, 1H), 7.45-7.40 (t,1H), 5.46-5.42 (d, 2H), 5.35-5.32 (d, 2H), 4.31-4.16 (m, 1H), 3.81-3.79(m, 6H), 2.64-2.60 (d, 3H), 2.46-2.40 (d, 3H), 2.07-1.98 (m, 2H),1.58-1.55 (m, 2H), 1.48-1.42 (m, 2H).

Example 13 Synthesis of4-(((1r,4r)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carboxamide(I-1)

Synthesis of4-(((1r,4r)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylicacid

A solution of ethyl3-[[4-(morpholin-4-yl)cyclohexyl]amino]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2,4,6,10,12-hexaene-12-carboxylate(100 mg, 0.23 mmol, 1.00 equiv) in 6 M aqueous HCl (20 mL) was stirredfor 2 h at 80° C. The resulting mixture was concentrated under vacuum togive 85 mg (crude) of4-(((1r,4r)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylicacid hydrochloride as a yellow solid.

Step 2. Synthesis of4-(((1r,4r)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carbonylchloride

A solution of4-(((1r,4r)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylicacid hydrochloride (85 mg, crude) in dichloromethane (5 mL) was addedthionyl chloride (4 mL) at room temperature under nitrogen. Theresulting solution was stirred for 2 h at 50° C. and concentrated undervacuum to give the resulted4-(((1r,4r)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carbonylchloride (80 mg, crude) as a yellow solid which was used directly fornext step without further purification.

Step 3. Synthesis of4-(((1r,4r)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carboxamide(I-1)

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of4-(((1r,4r)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carbonylchloride (40 mg, 0.09 mmol, 1.00 equiv) in dichloromethane (5 mL) at 0°C. under nitrogen. Then ammonia-THF (5 mL) was added via syringe and theresulting solution was stirred overnight at room temperature. Theresulting mixture was concentrated under vacuum. The crude product (50mg) was purified by Prep-HPLC with the following conditions (Waters):Column, Xbridge Prep C18, 5 um, 19*50 mm; mobile phase, Water with 0.05%NH₄HCO₃ and CH₃CN (10% CH₃CN up to 25% in 10 min, up to 95% in 1.5 min,down to 10% in 1.5 min); Flow rate: 20 mL/min; UV detection at 254/220nm. After collection and evaporation in vacuo, This resulted4-(((1r,4r)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carboxamide(19 mg, 50%) was obtained as a white solid. LC/MS (ES, m/z) 412 [M+H]⁺.¹H-NMR (300 MHz, DMSO): δ 1.36-1.44 (2H, m), 1.60-1.64 (2H, m),1.91-1.95 (2H, m), 2.10-2.13 (2H, m), 2.27-2.50 (1H, m), 2.50-2.72 (4H,m), 3.57-3.59 (4H, m), 4.24-4.26 (1H, m), 7.01-7.04 (1H, d), 7.58 (1H,s), 7.96-7.99 (1H, d), 8.14-8.21 (2H, m), 8.52-8.58 (2H, m).

Example 14 Synthesis of(4-(((1r,4r)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidin-6-yl)methanol(I-10)

A solution of ethyl4-(((1r,4r)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylate(80 mg, 0.18 mmol, 1.00 equiv) in 5 mL distilled THF was added LiAlH₄(20 mg, 0.53 mmol, 2.90 equiv) at 0° C. under nitrogen. The resultingsolution was stirred for 3 h at room temperature and quenched withNaSO₄.10H₂O. The solids were filtered out and washed with DCM for threetimes and the filtrate was concentrated under vacuum. The crude product(70 mg) was purified by Prep-HPLC with the following conditions(Waters): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, waterwith 0.05% NH₄CO₃ and CH₃CN (5.0% CH₃CN up to 42.0% in 10 min, up to95.0% in 2 min, down to 5.0% in 2 min); Flow rate: 20 mL/min; UVdetection at 254/220 nm. The product-containing fractions were collectedand evaporated to remove solvents under reduced pressure to give thedesired(4-(((1r,4r)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidin-6-yl)methanol(10.9 mg) as a white solid. LC/MS (ES, m/z) 399 [M+H]⁺. ¹H-NMR (300 MHz,CD₃OD): δ 1.51-1.71 (4H, m), 2.11-2.21 (2H, m), 2.21-2.29 (2H, m),2.31-2.38 (1H, m), 2.50-2.72 (4H, m), 3.71-3.79 (4H, m), 4.31-4.41 (1H,m), 4.81-4.85 (2H, s), 7.53-7.56 (1H, d), 7.94-7.97 (1H, d), 8.18 (1H,s), 8.45 (1H, s).

Example 15 Synthesis of4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-N-methylbenzo[4,5]thieno[2,3-d]pyrimidine-6-carboxamide(I-14)

Into a 10-mL sealed tube, was placed a solution of ethyl4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylate(100 mg, 0.25 mmol, 1.00 equiv) in 7 mL of methylamine-EtOH solution.The resulting solution was stirred for 5 h at room temperature andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with dichloromethane/methanol/NH₄OH (10:1:0.05) to give thedesired4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-N-methylbenzo[4,5]thieno[2,3-d]pyrimidine-6-carboxamide(49.3 mg, 51%) as a off-white solid. LC/MS: (ES, m/z) 357 [M+H]⁺. ¹H-NMR(300 MHz, CD₃OD) δ 1.72-1.83 (4H, m), 2.20-2.25 (2H, d), 2.33-2.38 (2H,d), 2.89 (6H, s), 3.01 (3H, s), 3.24-3.30 (1H, m), 4.44-4.46 (1H, m),7.93-7.96 (1H, d), 8.06-8.09 (1H, d), 8.50 (1H, s), 8.61 (1H, s).

Example 16 Synthesis of4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-N-ethylbenzo[4,5]thieno[2,3-d]pyrimidine-6-carboxamide(I-17)

Synthesis of4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylicacid

Into a 50-mL round-bottom flask, was placed ethyl4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylate(80 mg, 0.20 mmol, 1.00 equiv) and hydrogen chloride (6N) (20 mL). Theresulting solution was stirred for 4 h at 80° C. The resulting mixturewas concentrated under vacuum. This resulted in 65 mg (crude) of3-[[4-(dimethylamino)cyclohexyl]amino]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2,4,6,10,12-hexaene-12-carboxylicacid as a yellow solid.

Synthesis of4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carbonylchloride

To a solution of3-[[4-(dimethylamino)cyclohexyl]amino]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2,4,6,10,12-hexaene-12-carboxylicacid (80 mg, 0.22 mmol, 1.00 equiv) in dichloromethane (5 mL) was addedsulfurooyl dichloride (4 mL) and N,N-dimethylformamide (a catalyticamount). The resulting solution was stirred for 2 h at 45° C. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with PE/EA (1:1). This resulted in 80 mg (95%)of4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carbonylchloride as a light yellow solid.

Synthesis of4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-N-ethylbenzo[4,5]thieno[2,3-d]pyrimidine-6-carboxamide

To a solution of3-[[4-(dimethylamino)cyclohexyl]amino]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5,10,12-hexaene-12-carbonylchloride (80 mg, 0.21 mmol, 1.00 equiv) in dichloromethane (5 mL) wasadded ethylamine-THF (2M) (2 mL). The resulting solution was stirred for2 h at room temperature. The resulting mixture was concentrated undervacuum. he crude product (70 mg) was purified by Prep-HPLC with thefollowing conditions: Column, SunFire Prep C18, 19*150 mm 5 um; mobilephase, water with 50 mL NH₄HCO₃ and CH₃CN (5.0% CH₃CN up to 43.0% in 12min, up to 95.0% in 2 min, down to 5.0% in 2 min); Detector, uv 254/220nm. This resulted in 20.3 mg (25%) of4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-N-ethylbenzo[4,5]thieno[2,3-d]pyrimidine-6-carboxamideas a off-white solid. LC-MS: (ES, m/z): [M+H]⁺ 398. ¹H NMR (300 MHz,CD₃OD, ppm): δ 1.27 (t, J=7.2 Hz, 3H), 1.42-1.70 (m, 4H), 2.14 (d,J=17.4 Hz, 2H), 2.24 (d, J=17.4 Hz, 2H), 2.40-2.52 (m, 7H), 3.52 (q,J=7.2 Hz, 2H), 4.34-4.42 (m, 1H), 7.95 (d, J=8.4 Hz, 1H), 8.08 (d, J=8.4Hz, 1H), 8.49 (s, 1H), 8.57 (s, 1H).

Example 17 Synthesis of4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-N,N-dimethylbenzo[4,5]thieno[2,3-d]pyrimidine-6-carboxamide(I-19)

To a solution of3-[[4-(dimethylamino)cyclohexyl]amino]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5,10,12-hexaene-12-carbonylchloride (80 mg, 0.21 mmol, 1.00 equiv) and TEA (63.7 mg, 0.63 mmol,3.00 equiv) in DCM (10 mL) was added dimethylamine hydrochloride (33.5mg, 0.41 mmol, 2.00 equiv). The resulting solution was stirred for 2 hat room temperature. After evaporation, the crude product (100 mg) waspurified by Prep-HPLC with the following conditions: Column, SunFirePrep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH₄HCO₃ andCH₃CN (7.0% CH₃CN up to 63.0% in 13 min); Detector, 254/220 nm. Thisresulted in 26 mg (32%) of4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-N,N-dimethylbenzo[4,5]thieno[2,3-d]pyrimidine-6-carboxamideas a white solid. LC-MS: (ES, m/z): [M+H]⁺ 398. ¹H NMR (300 MHz, CD₃OD,ppm): δ 1.53-1.71 (m, 4H), 2.05 (d, J=10.5 Hz, 2H), 2.24 (d, J=10.5 Hz,2H), 2.30-2.45 (m, 7H), 3.08 (s, 3H), 3.19 (s, 3H), 4.34-4.39 (m, 1H),7.58 (d, J=8.4 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.34 (s, 1H), 8.56 (s,1H).

Example 18 Synthesis of2-(4-(((1r,4r)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidin-6-yl)ethanol(I-15)

A solution of ethyl2-(4-(((1r,4r)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidin-6-yl)acetate(100 mg, 0.22 mmol, 1.00 equiv) in 5 mL of anhydrous THF was addedLiAlH₄ (30 mg, 0.88 mmol, 4.03 equiv) in portions at 0° C. undernitrogen. The resulting mixture was stirred for 4 h at room temperatureand diluted with DCM, quenched with Na₂SO₄.10H₂O (2.0 g). The solidswere filtered out and the filtrate was concentrated under vacuum. Thecrude product was purified by Prep-HPLC with the following conditions(Waters): Column, Xbridge Prep C18, 5 um, 19*50 mm; mobile phase, waterwith 0.05% NH₄HCO₃ and CH₃CN (10% CH₃CN up to 70% in 8 min); Flow rate:20 mL/min; UV detection at 254/220 nm. The product-containing fractionswere collected and partially evaporated to remove water and CH₃CN underreduced pressure. The residue was lyophilized overnight to give thedesired product2-(4-(((1r,4r)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidin-6-yl)ethanol(17 mg, 19%) as a white solid. LCMS: (ES, m/z) 413 [M+H]⁺. ¹H-NMR (400MHz, CDCl₃): δ 8.53 (s, 1H), 7.85-7.83 (d, 1H), 7.64 (s, 1H), 7.38-7.36(d, 1H), 5.35-5.33 (d, 1H), 4.32-4.23 (m, 1H), 4.04-3.99 (dd, 2H), 3.78(s, 4H), 3.10-3.07 (t, 2H), 2.64 (s, 4H), 2.56-2.42 (d, 3H), 2.09-2.06(d, 2H), 1.98-1.95 (t, 1H), 1.61-1.52 (m, 2H), 1.48-1.28 (m, 2H).

Example 19 Synthesis of(4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidin-6-yl)methanol(I-7)

A solution of ethyl3-[[4-(dimethylamino)cyclohexyl]amino]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5,10,12-hexaene-12-carboxylate(80 mg, 0.20 mmol, 1.00 equiv) in 5 mL of distilled THF was added LiAlH₄(16 mg, 0.42 mmol, 2.10 equiv) at 0° C. under nitrogen. The resultingsolution was stirred for 2 h at room temperature. After completion, themixture was diluted with THF (50 mL) and quenched with Na₂SO₄.H₂O. Thesolids were filtered out and the filtrate was concentrated under vacuum.The residue was applied onto a silica gel column withdichloromethane/methanol/NH₄OH (5:1:0.05) to give 16.8 mg (23%) of thedesired(4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidin-6-yl)methanolas a white solid. LC/MS: (ES, m/z) 357 [M+H]⁺. ¹H-NMR (300 MHz, CD₃OD) δ1.56-1.85 (4H, m), 2.10-2.19 (2H, m), 2.29-2.33 (2H, m), 2.73 (6H, s),2.73-2.88 (1H, m), 4.32-4.37 (1H, m), 4.84 (2H, s), 7.53-7.55 (1H, d),7.95-7.97 (1H, d), 8.19 (1H, s), 8.46 (1H, s).

Example 20 Synthesis of(1r,4r)-N1-(benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)cyclohexane-1,4-diaminehydrochloride Synthesis of tert-butyl((1r,4r)-4-(benzo[4,5]thieno[2,3-d]pyrimidin-4-ylamino)cyclohexyl)carbamate

A solution of 4-chlorobenzo[4,5]thieno[2,3-d]pyrimidine (220 mg, 1.00mmol, 1.00 equiv) in 10 mL of DMF was added tert-butyltrans-N-(4-aminocyclohexyl)carbamate (320 mg, 1.49 mmol, 1.50 equiv) andtriethylamine (200 mg, 1.98 mmol, 2.00 equiv) and the resulting solutionwas stirred overnight at room temperature. The reaction was thenquenched with water, extracted with 3×50 mL of ethyl acetate. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:4) toafford tert-butyl((1r,4r)-4-(benzo[4,5]thieno[2,3-d]pyrimidin-4-ylamino)cyclohexyl)carbamate(0.25 g, 63%) as a white solid. LC/MS (ES, m/z): 399 (M+H⁺).

Step 2. Synthesis of(1r,4r)-N1-(benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)cyclohexane-1,4-diaminehydrochloride

A solution of tert-butyl((1r,4r)-4-(benzo[4,5]thieno[2,3-d]pyrimidin-4-ylamino)cyclohexyl)carbamate(500 mg, 1.25 mmol, 1.00 equiv) in dichloromethane (10 mL) was addedhydrochloric acid (12 M, 1 mL) at 0° C. The resulting solution wasstirred for 2 h at room temperature and concentrated in vacuo. The pHvalue of the solution was adjusted to 9 with sodium bicarbonate (1mol/L) and the solids were collected by filtration, and washed with 5 mLof water. After dried in an oven at 45° C. for 2 h, the desired(1r,4r)-N1-(benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)cyclohexane-1,4-diaminehydrochloride (362.4 mg, 86%) was obtained as a white solid. LC-MS: (ES,m/z) 299 (M+H⁺). ¹H-NMR: (400 MHz, CD₃OD) δ 8.48 (s, 1H), 8.27 (d, 1H),8.00 (d, 1H), 7.63-7.53 (m, 2H), 7.45-7.37 (m, 1H), 3.24-3.15 (m, 1H),2.30 (d, 2H), 2.18 (d, 2H), 1.79-1.66 (m, 4H).

Example 21 Synthesis of2-(((1r,4r)-4-(benzo[4,5]thieno[2,3-d]pyrimidin-4-ylamino)cyclohexyl)(methyl)amino)-1-(pyrrolidin-1-yl)ethanone(I-3)

A solution of 4-chlorobenzo[4,5]thieno[2,3-d]pyrimidine (300 mg, 1.36mmol, 1.00 equiv) in CH₃CN (25 mL) was added3-(4-aminocyclohexyl)-1-(pyrrolidin-1-yl)butan-1-one (937 mg, 3.93 mmol,3.00 equiv), potassium carbonate (1.88 g, 13.60 mmol, 10.00 equiv) andtriethylamine (411 mg, 4.06 mmol, 3.00 equiv) subsequently at roomtemperature under nitrogen. The resulting solution was stirred overnightat 50° C. in an oil bath and quenched with water. The resulting solutionwas extracted with 3×40 mL of ethyl acetate and combined organic layerswere washed with brine, dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with dichloromethane/methanol/NH₄OH (10:1:0.05) to afford2-(((1r,4r)-4-(benzo[4,5]thieno[2,3-d]pyrimidin-4-ylamino)cyclohexyl)(methyl)amino)-1-(pyrrolidin-1-yl)ethanone(232.3 mg, 40%) as a white solid. LC/MS: (ES, m/z) 424 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): δ 8.60 (s, 1H), 7.95-7.93 (d, 1H), 7.81-7.79 (d, 1H),7.58-7.49 (m, 2H), 5.36-5.34 (d, 1H), 4.32-4.28 (m, 1H), 3.57-3.50 (m,4H), 3.32 (s, 2H), 2.70 (m, 1H), 2.43-2.37 (m, 5H), 2.05-2.02 (m, 4H),2.00-1.91 (m, 2H), 1.89-1.86 (m, 2H), 1.63-1.54 (dd, 2H), 1.48-1.38 (m,2H).

Example 22 Synthesis of ethyl4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-5-carboxylate(I-22)

To a solution of ethyl3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5,10,12-hexaene-13-carboxylate(200 mg, 0.68 mmol, 1.00 equiv) and1-N,1-N-dimethylcyclohexane-1,4-diamine (195 mg, 1.37 mmol, 2.00 equiv)in butan-2-ol (10 mL) was added triethylamine (5 mL). The resultingsolution was stirred for 5 h at 90° C. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with dichloromethane/methanol (15:1-5:1). This resulted in 200 mg(73%) of ethyl4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-5-carboxylateas a white solid. LC-MS: (ES, m/z): [M+H]⁺ 399. ¹H NMR-(300 MHz, CDCl₃,ppm): δ 1.21-1.60 (m, 7H), 2.03 (d, J=12.3 Hz, 2H), 2.05-2.40 (m, 9H),4.27-4.32 (m, 1H), 4.54 (q, J=6.9 Hz, 2H), 5.30 (d, J=7.2 Hz, 1H), 7.62(t, J=7.8 Hz, 1H), 7.98 (d, J=7.5 Hz, 1H), 8.24 (d, J=7.5 Hz, 1H), 8.63(s, 1H).

Example 23 Synthesis of(4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidin-5-yl)methanol(I-23)

To a solution of ethyl3-[[4-(dimethylamino)cyclohexyl]amino]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5,10,12-hexaene-13-carboxylate(100 mg, 0.25 mmol, 1.00 equiv) in 5 mL of freshly distilled THF wasadded LiAlH₄ (11.4 mg, 1.20 equiv) at 0° C. under nitrogen. Theresulting solution was stirred for 2 h at room temperature and thenquenched by the addition of 0.1 mL of saturated aqueous NH₄Cl, dilutedwith 50 mL of EtOAc. The solids were filtered out and the filtrate wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with dichloromethane/methanol (20:1-5:1) to give the desired(4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidin-5-yl)methanol(65 mg, 72%) as a white solid. LC-MS: (ES, m/z): 358 [M+H]⁺. ¹H NMR (300MHz, D₂O): δ 1.31-1.43 (m, 2H), 1.53-1.64 (m, 2H), 1.98-2.12 (m, 4H),2.81 (s, 6H), 3.17-3.25 (m, 1H), 3.49-3.62 (m, 1H), 4.44 (s, 2H),7.10-7.25 (m, 3H), 7.75 (s, 1H).

Example 24 Synthesis of4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carboxamide(I-6) Synthesis of4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylicacid

Ethyl3-[[4-(dimethylamino)cyclohexyl]amino]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2,4,6,10,12-hexaene-12-carboxylate(100 mg, 0.25 mmol, 1.00 equiv) dissolved in 20 mL of 6 M hydrochloricacid was stirred for 4 h at 80° C. The resulting mixture wasconcentrated and dried in an oven under vacuum to give\4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylicacid (85 mg, crude) as a yellow solid.

Synthesis of4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carboxamide(I-6)

A solution of4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylicacid (80 mg, 0.22 mmol, 1.00 equiv), NH₄Cl (60 mg, 1.12 mmol, 5.19equiv) and 4-dimethylaminopyridine (30 mg, 0.25 mmol, 1.14 equiv) in 10mL of distilled DMF was added HOBt (40 mg, 0.30 mmol, 1.37 equiv) and,EDCI (60 mg, 0.39 mmol, 1.79 equiv) successively at room temperatureunder nitrogen. The resulting solution was stirred for 3 h at 40° C. anddiluted with DCM (100 mL). The organic phase was concentrated undervacuum. The crude product was purified by Prep-HPLC with the followingconditions (Waters): Column, Xbridge Prep C18, 5 um, 19*50 mm; mobilephase, water with 0.05% NH₄HCO₃ and CH₃CN (10% CH₃CN up to 25% in 10min, up to 95% in 1.5 min, down to 10% in 1.5 min); Flow rate: 20mL/min; UV detection at 254/220 nm. After collection of theproduct-containing fractions and evaporation in vacuo, the resulted4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carboxamide(39.9 mg, 50%) was obtained as a white solid. LC/MS: (ES, m/z): 370[M+H]⁺. ¹H-NMR (400 MHz, CD₃OD): δ 1.30-1.52 (2H, m), 1.58-1.69 (2H, m),2.08-2.11 (2H, m), 2.28-2.30 (2H, m), 2.39 (6H, s), 2.44-2.56 (1H, m),4.37-4.42 (1H, m), 8.01-8.03 (1H, d), 7.58 (1H, s), 8.09-8.11 (1H, d),8.50 (1H, s), 8.62 (1H, s).

Example 25 Synthesis ofN,N-dimethyl-4-(((1r,4r)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carboxamide(I-20)

Into a 25-mL round-bottom flask containing a solution of4-(((1r,4r)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carbonylchloride (40 mg, 0.09 mmol, 1.00 equiv) in anhydrous dichloromethane (5mL) was added dimethylamine-THF (5 mL) at 0° C. The resulting solutionwas stirred overnight at room temperature and concentrated under vacuum.The crude product (40 mg) was purified by Prep-HPLC with the followingconditions (Waters): Column, Xbridge Prep C18, 5 um, 19*50 mm; mobilephase, water with 0.05% NH₄HCO₃ and CH₃CN (10% CH₃CN up to 25% in 6 min,up to 95% in 2 min, down to 10% in 2 min); Flow rate: 20 mL/min; UVdetection at 254/220 nm. This resulted in 16.5 mg (40%) ofN,N-dimethyl-4-(((1r,4r)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidine-6-carboxamideas a white solid. LC/MS (ES, m/z): 440 [M+H]⁺. ¹H-NMR (400 MHz, DMSO): δ1.36-1.44 (2H, m), 1.60-1.64 (2H, m) 1.91-195 (2H, m), 2.10-2.13 (2H,m), 2.27-2.50 (1H, m), 2.50-2.72 (4H, m), 2.95 (3H, s), 3.07 (3H, s),3.58 (4H, m), 4.31 (1H, m), 7.07-7.09 (1H, d), 7.51-7.35 (1H, d),8.12-8.14 (1H, d), 8.45 (1H, s), 8.51 (1H, s).

Example 26 Synthesis of5-N-(1-methyl-1H-pyrazol-4-yl)-3-N-[trans-4-(morpholin-4-yl)cyclohexyl]-8-thia-4,6-diazatricyclo[7.4.0.0̂[2,7]]trideca-1(9),2,4,6,10,12-hexaene-3,5-diamine(I-89)

Synthesis of Compound 26.1.

Compound 3.2 (8 g, 35.51 mmol, 1.00 equiv) and urea (21.3 g, 354.67mmol, 10.00 equiv) were heated at 200° C. for 1 h. After cooling, theresulting solids was diluted with water and the pH value of the mixturewas adjusted to 14 with sodium hydroxide (2 M) and stirred for anadditional 2 h. The solids were removed by filtration and the filtratewas acidified to pH ˜2 with conc. hydrochloric acid. The precipitate wascollected by filtration and dried in an oven at 60° C. overnight to give4.0 g (crude) of 26.1 as a yellow solid. MS (ES): m/z 223 (M+H)⁺.

Synthesis of Compound 26.2.

Compound 26.2 was prepared from 26.1 in a manner analogous to the methoddescribed in Example 2, Step 2. Isolated a light yellow solid (2.8 g) in60% yield. MS (ES): m/z 259 and 261 (M+H)⁺.

Synthesis of Compound 26.3.

Compound 26.3 was prepared from 26.2 in a manner analogous to the methoddescribed in Example 2, Step 2. Isolated a white solid (200 mg) in 85%yield. MS (ES): m/z 407 and 409 (M+H)⁺.

Synthesis of Compound 26.4.

Into a 10-mL vial containing a mixture of 26.3 (100 mg, 0.25 mmol, 1.00equiv) in dry isopropanol (4 mL) was added 1-methyl-1H-pyrazol-4-aminehydrochloride (50 mg, 0.37 mmol, 1.50 equiv) and hydrochloric acid (4 Min dioxane, 0.2 mL). The sealed vial was reacted for 1.5 h at 140° C.under microwave. After completion, the resulting mixture wasconcentrated under vacuum and the residue was purified by chromatographyon silica gel column with dichloromethane/methanol/ammonia (15:1:0.1) togive 50 mg of desired compound. The pure 26.4 (38 mg) was obtained byprecipitation from DCM/hexane (1:10) as an off-white solid. MS (ES): m/z468 (M+H)⁺. ¹H NMR (300 MHz, d₆-DMSO) δ 8.84 (s, 1H), 7.78 (s, 1H), 7.43(s, 1H), 5.63 (s, 1H), 4.01-3.98 (m, 1H), 3.78 (s, 3H), 3.52-3.61 (m,4H), 2.90-2.81 (m, 2H), 2.66-2.59 (m, 2H), 2.29-2.20 (m, 1H), 3.57 (m,3H), 2.14-2.05 (m, 2H), 1.9-1.75 (m, 6H), 1.52-1.30 (m, 4H).

Synthesis of Compound I-89.

Compound I-89 was prepared from compound 26.4 (240 mg) in a manneranalogous to the method described in Example 2, Step 1. Isolated 20 mgof a gray solid. MS (ES): m/z 464.4 (M+H)⁺.

Additional compounds of the invention can be prepared in a mannersimilar to those exemplified above. Furthermore, additional syntheticroutes to compounds analogous to those of the present invention can befound in PCT/US13/20981 and WO2012097013, the entirety of both of whichis incorporated herein by reference.

Example 27 IRAK-4 Assay Assay Materials

Material Vendor Catalogue number HEPES Amresco 0511 Brij-35 SigmaB4184-100mL Coating Reagent #3 Caliper EDTA Sigma E5134-1KG ATP SigmaA7699-1G MgCl₂ Sigma 63068-250G MnCl₂ Sigma M8054-100G Peptide 8 GLbioscience 112396 IRAK4 CARNA Bioscience 09-145 384-well plate Corning3573

A 1× kinase base buffer was prepared from 50 mM HEPES, pH 7.5 and0.0015% Brij-35. A stop buffer was prepared from 100 mM HEPES, pH 7.5,0.015% Brij-35, 0.2% Coating Reagent #3, and 50 mM EDTA.

Test compound was diluted to 50× of the final desired highest inhibitorconcentration in reaction by 100% DMSO. 100 ul of this compound dilutionwas transferred to a well in a 96-well plate. For example, if desiredhighest inhibitor concentration in IC50 determination is 100 uM, thenprepare 5000 uM of compound DMSO solution in this step.

Test compound was serially diluted by transferring 30 μl to 60 μl of100% DMSO in the next well and so forth for a total of 10concentrations. 100 μl of 100% DMSO was added to two empty wells for nocompound control and no enzyme control in the same 96-well plate.

A new 96-well plate was marked as intermediate plate. 5 μl of compoundserial dilution was transferred from source plate to the correspondingwells of the intermediate plate. 45 μl of 1× kinase base buffer (KBbuffer) was added to each well of the intermediate plate. Theintermediate plate was placed for 10 min on a shaker.

5 μl of each well was transferred from the 96-well intermediate plate toa 384-well plate in duplicates. For example, A1 of the 96-well plate istransferred to A1 and A2 of the 384-well plate. A2 of the 96-well plateis transferred to A3 and A4 of the 384-well plate, and so on.

IRAK4 and DTT in 1× kinase base buffer was added. The 2.5× enzyme mixcontained 8.8 nM IRAK4 and 5 mM DTT.

Peptide 8, ATP, MgCl₂ and MnCl₂ were added in the 1× kinase base buffer.The 2.5× peptide mix contained 3.75 μM peptide 8, 92.5 μM ATP, 12.5 mMMgCl₂ and 2.5 mM MnCl₂.

Assay plate already contained 5 μl of compound in 10% DMSO. Added 10 μlof 2.5× enzyme solution to each well of the 384-well assay plate, exceptno enzyme control wells. The final concentration of IRAK4 in reactionwas 3.5 nM. Added 10 μl of 1× kinase base buffer to no enzyme controlwells in the assay plate. Incubated at room temperature for 10 min.

Added 10 μl of 2.5× peptide solution to each well of the 384-well assayplate. The final concentration of Peptide 8 and ATP was 1.5 μM and 37μM, respectively. Incubated at 28° C. for 40 minutes. Added 25 μl ofstop buffer to stop reaction. Collected data on Caliper.

Copied conversion % data from Caliper program. Converted conversion %values to percent inhibition values. Percent inhibition=(max−conversion%)/(max−min)*100, where “max” means the conversion % of DMSO control and“min” means the conversion % of no enzyme control.

Table 3 shows the activity of selected compounds of this invention inthe IRAK-4 activity inhibition assay. The compound numbers correspond tothe compound numbers in Table 1. Compounds having an activity designatedas “A” provided an IC₅₀≦0.1 μM; compounds having an activity designatedas “B” provided an IC₅₀ of 0.1-1 μM; compounds having an activitydesignated as “C” provided an IC₅₀ of 1-10 μM; and compounds having anactivity designated as “D” provided an IC₅₀≧10 μM. “NA” stands for “notassayed.”

TABLE 3 IRAK-4 Activity Inhibition Data Cpd # IRAK-4 I-1 A I-2 A I-3 AI-4 A I-5 A I-6 A I-7 B I-8 B I-9 B I-10 B I-11 B I-12 B I-13 B I-14 BI-15 B I-16 B I-17 B I-18 C I-19 C I-20 C I-21 C I-22 D I-23 D

Provided compounds can also be assayed as inhibitors of IRAK-1 by thesame protocol used for IRAK-4 above, substituting IRAK-1 for IRAK-4.

Provided compounds can also be assayed in a panel of kinases todetermine their selectivity for IRAK-4.

Provided compounds can also be assayed to determine their K_(i) versusIRAK-4 using a Reaction Biology radioactive kinase assay.

Example 28 Cytokine Production Assay

Provided compounds were also assayed in an LPS (Lipopolysaccharide) orR848 (TLR-7 agonist) induced cytokine (e.g. TNFα and IL8) productionassay in THP-1 cells, human peripheral blood mononuclear cells (hPBMC),and whole blood. The exemplary protocol for this assay in THP-1 cellswas as follows below.

THP-1 cells from ATCC (TIB-202) were cultured in RPMI Medium 1640(Invitrogen, Cat No. A10491-01), 10% fetal bovine serum (Invitrogen, CatNo. 10099141, Lot No. 8172882) containing 100 U/mL Penicillin, 100 μg/mLstreptomycin (Invitrogen, Cat No. 15140-122), and 50 uM2-Mercaptoethanol (Invitrogen, Cat No. 21985023). LPS-EK ultra pure(Invivogen, Cat No. tlrl-peklps) was used to induce IL8 and TNFαproduction, that is detected in the cell culture supernatant by IL8 HTRFkit (Cisbio, Cat No. 62IL8PEB) and TNFα HTRF kit (Cisbio, Cat No.62TNFPEB), as per manufacturer instructions. Cells were cultured in 96well assay plates at 100,000 cells per well, and compounds diluted infinal 0.3% DMSO were pre-incubated with cells for 1 hour prior tostimulation with 300 ng/mL LPS. Cytokine production in cell supernatantwas measured at 5 hours for TNFα and IL8 production, and for 16 hoursfor IL8 production and assessment of cell viability.

Table 4 shows the activity of selected compounds of this invention inthe Cytokine Production Assay. The compound numbers correspond to thecompound numbers in Table 1. Compounds having an activity designated as“A” provided an IC₅₀≦1 μM; compounds having an activity designated as“B” provided an IC₅₀ of ≧1 μM. “NA” stands for “not assayed.”

TABLE 4 Results of Cytokine Production Assay Compound TNF (5 h) IL-8 (16h) I-2 A A I-5 A A I-7 B A I-4 A A I-3 B A I-1 A A I-6 B A I-9 B A

Example 29 In Vivo LPS-Induced Model of Cytokine Production

Compounds of the present invention can also be evaluated in rats in anin vivo efficacy model for inhibiting LPS-mediated cytokine production.An exemplary protocol for this assay follows.

Drugs to be tested are formulated in 10% HP-β-CD in saline for i.p.injection. Male Wistar rats (180-220 g) are divided into 8 groups; everygroup except naive group has 10 rats at random as follows, and the ratsin all groups (group A to H) are fasted overnight.

Group number treatment Measurement A) Naive 5 Vehicle I.P. + 30 minlater PBS i.v. + 1 h later Rat TNF-a blood + 1 h later blood B) Model 10Vehicle I.P. + 30 min later LPS i.v. + 1 h later Rat TNF-a blood + 1 hlater blood C) dexamethasone 10 5 mg/kg dexamethasone I.P. + 30 minlater Rat TNF-a LPS i.v. + 1 h later blood + 1 h later blood D) 1 mg/kgdrug 10 1 mg/kg drug I.P. + 30 min later LPS i.v. + 1 h Rat TNF-a laterblood + 1 h later blood E) 3 mg/kg drug 10 3 mg/kg drug I.P. + 30 minlater LPS i.v. + 1 h Rat TNF-a later blood + 1 h later blood F) 10 mg/kgdrug 10 10 mg/kg drug I.P. + 30 min later LPS i.v. + 1 h Rat TNF-a laterblood + 1 h later blood G) 30 mg/kg drug 10 30 mg/kg drug I.P. + 30 minlater LPS i.v. + 1 h Rat TNF-a later blood + 1 h later blood H) 100mg/kg drug 10 100 mg/kg drug I.P. + 30 min later LPS i.v. + Rat TNF-a 1h later blood + 1 h later blood

Vehicle or drug is dosed i.p. 30 min prior to LPS/PBS challenge. LPS orPBS is injected intravenously through the tail vein. 1-2 mL of blood arecollected at 1 h and 2 h post LPS challenge by retro-orbital puncture byusing 5 mL tube coated with heparin saline (5 Uml/l). Collect plasma andfreeze it in −80° C. until TNF-α is analyzed by ELISA. LC/MS bioanalysisfor drug exposure is performed for a total of 150 samples for eachassay.

Example 30 In Vitro LPS/R848/CpG-Induced Cytokine Production Assays inhPBMC or Whole Blood

Compounds of the present invention can also be studied in in vitroLPS/R848/CpG-induced cytokine production assays. Exemplary protocolsfollow.

Whole Blood (LPS): 13 mL of whole blood solution is prepared bycombining whole blood in no serum medium with a ratio of 1:1. Cells areseeded in a 96-well plate with 130 ul/well of the cell suspensionaccording to the plate map. 9 ul of 30 mM compound solution is addedinto the wells in the assigned rows, then serial solutions with 4×dilutions are made. That is, add 9 ul of 100% DMSO into each of the restwells and take 3 ul of compound solution from the one-step higherconcentration solution and mix well with the DMSO. For the secondcompound master plate, 196 uL of the growth medium (no serum media) areadded into each of the wells and 4 uL of the compound solution from thefirst compound master plate is added and mixed with the media. Cells aretreated for 0.5 h by adding 20 ul of the compound and the controlsolutions prepared in the second master plate to each well according tothe plate map. Cells are stimulated with a) 1 ug/ml of LPS for 5 h(prepared a LPS solution with a concentration of 4 ug/ml in no serummedia and added 50 ul into each well); b) 0.1 ug/ml of LPS for 20 h(preparing a LPS solution with a concentration of 0.4 ug/ml in no serummedia and adding 50 ul into each well). Plates are sealed with sealingfilms and the plates are centrifuged at 3000 rpm at 4 degrees C. for 5min. The supernatants are transferred, and 100 ul of working Captureantibody solution is added to each well. The plates are sealed andincubated overnight at RT. IL-6, IFN-alpha or TNF-alpha detectionantibody labeled with biotin: Add 100 ul of the Detection Antibodysolution to each well. Cover the plate and incubate for 2 h at RT. Add100 ul of Streptavidin-HRP solution to each well. Cover the plate andincubate for 20 min at RT in dark. Add 100 ul of Substrate Solution toeach well. Incubate for 20 min at RT in dark. Add 50 ul of Stop Solutionto each well. Gently tap the plate to ensure thorough mixing. Determinethe optical density of each well immediately, using a microplate readerset to 450 nm and also read at 540 nm or 570 nm for correction ifwavelength correction is not available.

For R848-induced or CpG-induced assays, the same procedure as above isfollowed except that 1 uM R848 for 5 h, 0.5 uM R848 for 20 h, or 0.5 CpGfor 5 h or 20 h are used respectively instead of LPS.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

We claim:
 1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 3-7membered saturated or partially unsaturated carbocyclic ring or a 4-7membered saturated or partially unsaturated heterocyclic ring having 1-3heteroatoms independently selected from nitrogen, oxygen, and sulfur; nis 0-4; each R¹ is independently —R, halogen, —CN, —NO₂, —OR, —CH₂OR,—SR, —N(R)₂, —S(O)₂R, —S(O)₂N(R)₂, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂,—C(O)N(R)—OR, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)₂, Cy, or—N(R)S(O)₂R, or R¹ is selected from one of the following formulas:

 or two R¹ groups are taken together with their intervening atoms toform an optionally substituted 4-7 membered fused, spiro-fused, orbridged bicyclic ring having 0-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; each Cy is an optionally substituted ringselected from a 3-7 membered saturated or partially unsaturatedcarbocyclic ring or a 4-7 membered saturated or partially unsaturatedheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, and sulfur; each R is independently hydrogen, or anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, 4-7membered saturated or partially unsaturated heterocyclic having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur, or5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, or: two R groups on the samenitrogen are taken together with their intervening atoms to form a 4-7membered saturated, partially unsaturated, or heteroaryl ring having 0-3heteroatoms, in addition to the nitrogen, independently selected fromnitrogen, oxygen, and sulfur; Ring B is selected from a benzo fused ringand a 5-6 membered heteroaromatic fused ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, and sulfur; wherein saidRing B may be optionally substituted by one or more oxo, thiono, orimino groups; m is 0-4; p is 0-2; W is N or —C(R³)—; R^(z) is R, CN,NO₂, halogen, —C(O)N(R)₂, —C(O)OR, —C(O)R, —N(R)₂, —N(R)C(O)OR,—N(R)C(O)N(R)₂, —OR, or —S(O)₂N(R)₂; R³ is hydrogen, halogen, —CN, C₁₋₄aliphatic, C₁₋₄ haloaliphatic, —OR, —C(O)R, or —C(O)N(R)₂; L¹ is acovalent bond or a C₁₋₆ bivalent hydrocarbon chain wherein one or twomethylene units of the chain are optionally and independently replacedby —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —O—,—C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)₂—; each L² isindependently a covalent bond or a C₁₋₆ bivalent hydrocarbon chainwherein one or two methylene units of the chain are optionally andindependently replaced by —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—,—S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)₂—; andeach R⁴ is independently halogen, —CN, —NO₂, —OR, —SR, —N(R)₂, —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, —C(O)R, —CO₂R, —C(O)N(R)₂, —N(R)C(O)R,—N(R)C(O)N(R)₂, —C(O)N(R)OR, —N(R)C(O)OR, —N(R)S(O)₂N(R)₂, —N(R)S(O)₂R,or an optionally substituted group selected from C₁₋₆ aliphatic, phenyl,4-7 membered saturated or partially unsaturated heterocyclic having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur, or5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, or: two -L²(R⁴)_(p)—R⁴groups are taken together with their intervening atoms to form anoptionally substituted 4-7 membered fused, or bridged bicyclic ringhaving 0-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur.
 2. The compound of claim 1, wherein said compound is of formulaII:

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim2, wherein said compound is formula III:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim3, wherein said compound is of formula IV:

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim4, wherein said compound is of formula V:

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim3, wherein said compound is of formula VI:

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim2 wherein m is
 0. 8. The compound of claim 1, wherein Ring B is a6-membered heteroaromatic fused ring having 1-2 nitrogens, or apharmaceutically acceptable salt thereof.
 9. The compound of claim 1,wherein Ring B is a 5-membered heteroaromatic fused ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur; ora pharmaceutically acceptable salt thereof.
 10. The compound of claim 1,wherein said compound is selected from any one of the compounds depictedin Table 1, or a pharmaceutically acceptable salt thereof.
 11. Apharmaceutical composition comprising a compound according to claim 1,and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
 12. Amethod of inhibiting an IRAK protein kinase in a patient or biologicalsample comprising administering to said patient, or contacting saidbiological sample with a compound according to claim 1, or apharmaceutical composition thereof.
 13. The method of claim 12, whereinthe IRAK protein kinase is an IRAK-4 protein kinase.
 14. The method ofclaim 12, wherein the IRAK protein kinase is an IRAK-1 protein kinase.15. A method of treating an IRAK-mediated disorder, disease, orcondition in a patient comprising administering to said patient acompound according to claim 1, or a pharmaceutical composition thereof.16. The method of claim 15, wherein the IRAK-mediated disorder, diseaseor condition is selected from the group consisting of a cancer, aneurodegenerative disorder, a viral disease, an autoimmune disease, aninflammatory disorder, a hereditary disorder, a hormone-related disease,a metabolic disorder, conditions associated with organ transplantation,immunodeficiency disorders, a destructive bone disorder, a proliferativedisorder, an infectious disease, a condition associated with cell death,thrombin-induced platelet aggregation, liver disease, pathologic immuneconditions involving T cell activation, a cardiovascular disorder, and aCNS disorder.
 17. The method of claim 16, wherein the cancer orproliferative disorder is selected the group consisting of a benign ormalignant tumor, solid tumor, carcinoma of the brain, kidney, liver,adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon,rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinarytract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas,neuroblastomas, multiple myeloma, gastrointestinal cancer, especiallycolon carcinoma or colorectal adenoma, a tumor of the neck and head, anepidermal hyperproliferation, psoriasis, prostate hyperplasia, aneoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma,keratoacanthoma, epidermoid carcinoma, large cell carcinoma,non-small-cell lung carcinoma, lymphomas, Hodgkins and Non-Hodgkins, amammary carcinoma, follicular carcinoma, undifferentiated carcinoma,papillary carcinoma, seminoma, melanoma, an IL-1 driven disorder, anMyD88 driven disorder, Smoldering of indolent multiple myeloma, orhematological malignancies (including leukemia, diffuse large B-celllymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chroniclymphocytic lymphoma, primary effusion lymphoma, Burkittlymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocyticleukemia, lymphoplasmacytic lymphoma, Waldenström's macroglobulinemia(WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma,and intravascular large B-cell lymphoma).
 18. The method of claim 17,wherein the MyD88 driven disorder is selected from the group consistingof ABC DLBCL, Waldenström's macroglobulinemia, Hodgkin's lymphoma,primary cutaneous T-cell lymphoma and chronic lymphocytic leukemia. 19.The method of claim 17, wherein the IL-1 driven disorder is Smolderingof indolent multiple myeloma.
 20. The method of claim 16, wherein theneurodegenerative disease is selected from the group consisting ofAlzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,Huntington's disease, cerebral ischemia, and neurodegenerative diseasecaused by traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy,treatment of diabetes, metabolic syndrome, obesity, organtransplantation and graft versus host disease.
 21. The method of claim16, wherein the inflammatory disorder is selected from the groupconsisting of conditions of the eye such as ocular allergy,conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis;diseases affecting the nose including allergic rhinitis; andinflammatory disease in which autoimmune reactions are implicated orhaving an autoimmune component or etiology, including autoimmunehematological disorders (e.g. hemolytic anemia, aplastic anemia, purered cell anemia and idiopathic thrombocytopenia), systemic lupuserythematosus, rheumatoid arthritis, polychondritis, scleroderma,Wegener granulamatosis, dermatomyositis, chronic active hepatitis,myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmuneinflammatory bowel disease (e.g. ulcerative colitis and Crohn'sdisease), irritable bowel syndrome, celiac disease, periodontitis,hyaline membrane disease, kidney disease, glomerular disease, alcoholicliver disease, multiple sclerosis, endocrine ophthalmopathy, Grave'sdisease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis,multiple sclerosis, primary biliary cirrhosis, uveitis (anterior andposterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernalkeratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis,systemic juvenile idiopathic arthritis, nephritis, vasculitis,diverticulitis, interstitial cystitis, glomerulonephritis (with andwithout nephrotic syndrome, e.g. including idiopathic nephrotic syndromeor minal change nephropathy), chronic granulomatous disease,endometriosis, leptospiriosis renal disease, glaucoma, retinal disease,ageing, headache, pain, complex regional pain syndrome, cardiachypertrophy, musclewasting, catabolic disorders, obesity, fetal growthretardation, hypercholesterolemia, heart disease, chronic heart failure,mesothelioma, anhidrotic ecodermal dysplasia, Behcet's disease,incontinentia pigmenti, Paget's disease, pancreatitis, hereditaryperiodic fever syndrome, asthma (allergic and non-allergic, mild,moderate, severe, bronchitic, and exercise-induced), acute lung injury,acute respiratory distress syndrome, eosinophilia, hypersensitivities,anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases,COPD (reduction of damage, airways inflammation, bronchialhyperreactivity, remodeling or disease progression), pulmonary disease,cystic fibrosis, acid-induced lung injury, pulmonary hypertension,polyneuropathy, cataracts, muscle inflammation in conjunction withsystemic sclerosis, inclusion body myositis, myasthenia gravis,thyroiditis, Addison's disease, lichen planus, Type 1 diabetes, or Type2 diabetes, appendicitis, atopic dermatitis, asthma, allergy,blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,cholangitis, cholecystitis, chronic graft rejection, colitis,conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis,encephalitis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitissuppurativa, immunoglobulin A nephropathy, interstitial lung disease,laryngitis, mastitis, meningitis, myelitis myocarditis, myositis,nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis,parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis,pneumonitis, pneumonia, polymyositis, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis,vasculitis, vulvitis, alopecia areata, erythema multiforma, dermatitisherpetiformis, scleroderma, vitiligo, hypersensitivity angiitis,urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus,paraneoplastic pemphigus, epidermolysis bullosa acquisita, acute andchronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis,rheumatoid arthritis, Juvenile rheumatoid arthritis, CryopyrinAssociated Periodic Syndrome (CAPS), and osteoarthritis.